>> I'm going to run
the class as follows.
I'll have the most
important announcements
at the very beginning
of the class.
So I'll be talking about
stuff like, what's covered
on the midterm, what's expected
from your proposal assignment
et cetera at the very beginning.
So, you definitely want
to show up on time,
show up early get a sit,
be prepare because most
important stuff is going to be
in that first five minutes.
OK. Oh, and by the way,
feel free to interrupt
if you have any questions.
OK. So, don't hesitate to
interrupt if anything comes up.
OK. So some announcements
today, and again,
announcements will come
out at the very beginning
of each class.
Our reading assignments
this week,
I like you to obtain a textbook,
it's available on the bookstore,
there are big stack of them
when I visited last week.
>> They ran out.
>> They ran out?
Oh, well it's good.
OK. If they ran out,
Amazon.com has them on sale
and you can get them
delivered very quickly.
OK. And I know for while,
Amazon was selling them
at some ridiculous discount, so.
I know because as one of the
co-authors, I'm very interested
in how they're selling.
Along those lines, as one of
the co-authors, I'm planning
to donate the profits
of the book to anyone
in this classroom
back to UCI for--
to support research
in chemistry.
OK. So, I'm requiring
a book that I wrote.
I'm obviously aware that I'm
going to profit from that.
The profits will go
back to UC Irvine.
OK. So if you have a
copy of the course reader
from previous years,
please throw it away.
OK. It's not going
to be any good.
I mean it's good, but I've
changed the material quite a bit
and the textbook is
significantly improved,
the problems are
slightly different.
I think it's-- the figures
are much better, et cetera.
And of course it was edited.
So, the course reader
for previous years is
not going to carry you.
You need to buy a
copy of the textbook.
So, Natalie how does
the sound sound?
>> It sounds great
and I'm sorry.
Just one quick announcement.
I know this is [inaudible]
tiny words could be difficult.
So, we can just work on not
having to come back here
since I had like 10
minutes to set up.
And just go through the
classroom on that side,
it would be it would
super helpful [inaudible].
The benefit is though to you
that probably [inaudible]
lecture.
All of these lectures will
be available in YouTube.
>> Cool.
>> So, if you can bear with all
my equipment then you can watch
these and enjoy them
as many times you want.
>> Thank you Nathalie.
Yeah. So, yes, they will
be posted online for you.
So, you can enjoy them and
study from them et cetera.
The goal here is that
you UC Irvine is one
of the very first Universities
to have both lecture class
and the laboratory class
in chemical biology.
We started these back in 2000
when I was an assistant
professor.
And since that time, we've
obviously built up quite a bit
in terms of our sophistication
of presenting the subject.
And so my goal is to
really bring that level
to other universities around the
world and around the country.
So, any that's why
we're doing this.
But it also has some
benefits to you as well.
OK. So reading assignment
for the first week.
Read Chapter 1.
I'm going to be covering all
the material in Chapter 1
so there's nothing for
you to skim through
or anything like that.
On future chapters,
there will be stuff
that I won't be covering and
I'll tell you when that happens.
OK. And you'll notice
when it happens.
OK. If you want to get a
head, start reading Chapter 2.
Chapter 1 is pretty basic.
Chapter 2 then starts
getting more advanced.
Homework. Do the
problems in Chapter 1,
all of the odd problems and also
all of the asterisked problems
and let me add that do this.
So, all the problems that
have an asterisk are--
the answers to all the problems
with an asterisk are
available online.
So, I'd like you to
do those as well.
OK. And then in addition,
we'll be posting a worksheet,
number 1, on the website.
It's not there yet but it'll be
posted very-- oh, it is there?
>> Well, it'll be
this afternoon.
>> It'll be posted afterwards.
OK. So, we'll be posting that.
That will form the basis
for the discussion sections.
Please work the worksheet
as well.
OK. So, before I get
started, before I delve
through very much more.
I want to tell you what
you should be paying
attention towards.
The first thing are
these announcements
that I'm giving you.
What's discussed in lecture?
The discussions that I give
you in lecture are your guide
to what I think it's important.
OK. So, right before the
midterm, you're going to want
to know, what do I need
to know on the midterm
to get an A in this class?
And my answer is always
the same which is,
what did I talked
about in lecture?
What I talk about in lecture
is what I think is important.
I have a limited amount of
time for these lectures.
I'll be doing two
lectures per chapter
of an hour and 20 minutes each.
And so, if I talk
about it in lecture,
I'm telling you I think
this is important.
This is something you need
to know for the midterm.
OK. So, what's discussed in
lecture is super important.
This includes both slides and
anything else that's posted
to the website, discussion
worksheets
and then the discussion
in discussion as well.
If you're sitting on the
left side of the classroom,
can I ask you to sort of scooch
in if you have an empty
chair on your right.
So, just to create
some more extra chairs
because we have people
that are arriving late.
So, just sort of
scooch over please.
Thank you.
OK. The next most important
thing is assigned reading.
But filter the assigned
reading through the filter,
through the lens of what
I talk about in class.
If I talk about it in class
that's telling you it's
important, if I don't talked
about it, less important.
And then finally, the problems
in the textbooks
as least important.
Good news, there's a few things
that you don't have
to worry about.
The first of these are
references on the slides.
I find it almost
impossible to do stuff
without having some referral
back to the literature.
That's sort of the
nature of scholarship
and it totally impossible to
get me to stop doing this.
When Dave and I wrote the
textbook, for example,
we had a list of references
that's like 10 times longer
than the one that's
posted to the website.
And we found it totally
impossible,
the publisher told
us to stop doing it,
to leave out those references.
And so, references are
basically the currency
that underpins what
I'm telling you.
But on the other hand, this
is an introductory class.
So, don't get worried
about those.
OK. If you take a graduate
class and they have references
on slides, you'll want to
look up those references.
But on an undergraduate level
don't get worked up about it.
OK. So, don't stress
about those.
In addition, don't stress
about stuff that's covered
in the textbook that we
don't discuss in class.
OK. So if I, you know,
I've said this before.
If I don't discuss
it class and it's
in the textbook,
don't worry about it.
OK. So, the text
is written as sort
of an advanced undergraduate
early graduate level.
And there's material there
that's frankly graduate level.
But I don't want you to
get stressed out about it.
OK. So, if don't talk about
it in class, that's my signal
that I don't think it's so
important for you to learn.
OK. Any question about
what I'm telling you?
Hey.
>> Are there any textbooks
reserved in the library?
>> That's a good question.
What is your name?
>> David.
>> David. Mariam, could you
look into that for David?
>> I know there're not yet
but they are ordering them.
So as soon as they got them--
it should be within
the next two weeks.
>> OK. So, they'll be--
eventually they'll
appear there but not yet.
>> Thank you
>> OK. Thanks for asking.
Other question?
What is your name?
[ Inaudible Remark ]
No, so we will not be
collecting the problem sets.
We'll have plenty of
other chances to learn
about your intelligence
and creativity.
So another question?
>> Will the slides be
posted ahead of time or--
>> Slides will be posted--
that's a good question.
I'll try. But I'm usually
frantically getting ready
the day.
So I'll do my best.
Certainly the Thursday
lecture will be.
But maybe not the Tuesday.
I'll do my very best though.
Other questions?
OK. More background.
Course instructors,
I'm Professor Weiss.
I've been teaching this
class for about 12 years.
And I absolutely love
chemical biology.
It's what makes me run to work.
It is my sole passion in life.
That's a little bit of an
exaggeration, but close.
OK. So what else would
you like to know about me?
Here's your chance.
For the next five minutes you
can ask anything you want,
personal, not so personal.
Go ahead in the back first.
So, my laboratory
is at the interface
of chemistry and biology.
And we're trying to
develop new ways of looking
at individual molecules
and dissecting how
membrane proteins work.
Thanks for asking.
And a question over here?
[ Inaudible Remark ]
It was. I'm kind of
a competitive guy.
I like driving fast
I like racing.
So, yeah. Question over here?
>> What's difference
between biochemistry
and chemical biology?
>> Chemical biology emphasize--
so, this is a great questions.
So, the question was
what is the difference
between biochemistry
and chemical biology?
Chemical biology
emphasizes what's happening
at the level of atoms and bonds.
And biochemistry
emphasizes what's happening
at a larger scale.
So, in biochemistry, my
colleagues are content to look
at proteins as sort
of large molecules
without getting too worked
up about hydrogen bond here
and hydrogen bond there.
Sometimes they get worked
up about those things.
But most of the time,
the diagram--
signal transduction
diagrams and things
like that are just large blobs.
And in this class, we'll
be zooming in and looking
at the actual atoms and bonds.
OK, good question.
OK. Anything else personal?
This is your last chance,
ask me anything personal.
Ask me about my pets, my
hobbies, oh, go ahead.
[ Inaudible Remak ]
No, I wish I did.
I only get to go
out once a year.
It's kind of the limitation.
So thanks for asking.
OK. Well, I should also let
you know I have two cats.
I'm married and that's it
for the personal information.
OK. OK. Last question, go ahead.
>> How many kids you have?
>> I have zero kids.
That's why I have
a two-sitter car.
[ Laughter ]
OK. You guys, that's it on the
personal stuff, enough about me.
I'm very pleased
that this quarter,
we have really the very best
TAs in the chemistry department.
I've gone through and
I've handpicked TAs,
Mariam Ifftikhar is
a great examplist.
Mariam and I taught
this class last year
and she knows everything there
is to know about this topic.
Her research is in
chemical biology
and she's absolutely superb.
If she tells you something
about the class, you could take
that as good as coming from me.
OK. In addition, our second TA,
Krithika Mohan isn't here today.
She's been tied up in India.
But she'll be back in
the next week or so.
And she's also a great
source of information.
She's also a graduate
student in my laboratory.
OK. So, we're lucky to have
California's finest natural
resource TAing for us,
Krithika and Mariam.
OK. So, in terms
of office hours,
I will be having two
office hours a week,
my Thursday office hours is set.
My Wednesday office hour,
however, will float.
OK. So, I will always have
office hours Thursday,
11 to noon.
This other office hour, the
second office hour will float,
meaning that my schedule
is constantly changing.
And so I'll have to
change this around.
OK. So, every week,
I will announce
when that office
hour will take place.
If for example, my office
hours don't fit your schedule,
tell me at the beginning
of the week when you
like my officer hour to be.
And I'll do my best to
accommodate as many people
as possibly each week.
OK. So, first office hour fixed,
second office hour floating.
I will always have the office
hours set up in away that's
at the interfaces
between classes.
So, you don't have to attend
the whole office hour,
if you can attend just the first
15 minutes or so or 10 minutes
and then fly off to your
class, that's perfectly OK.
Show up for five minutes,
get your question answered
and then disappear, I
don't care, I don't mind.
But I'll always set them up so
they're kind of at the junction
between classes that way
then it's less likely
that you'll be able to tell
me that you have a schedule
in conflict with everyone
in my office hours.
I've heard that before and
I usually ask those people
to show me their
schedule classes.
And I've never seen
it actually that way,
especially since I've the
second office hour floating.
So there's going to
be plenty of time
for you to meet this quarter.
And in fact I really
want to get to know you.
OK. I will get to know the names
of 95 percent of
you in this room.
I will know something about what
your career aspirations are.
I will know something about
your creativity in terms
of your ability to come
up with noble ideas,
your writing ability, and a lot
of other characteristic as well.
So, at the end of
this, I will be able
to write a very good letter
of recommendation for you.
OK. This is not [inaudible] the
last topic, but I would like you
to shutoff your cellphones
please.
OK. And that also includes
text messaging as well.
Thank you.
OK. So anyway, come out to
my office hours especially
in the first couple of
weeks, introduce yourself.
Tell me why it is
you're taking this class.
What it is you hope you learn?
What it is that you're hoping
to do once you graduate
from UC Irvine.
And if there's anything
I can do to help you
in that course, I will do it.
OK. That's one of my jobs.
And furthermore, even after
you graduate from this class,
you can still keep
in touch with me.
You can still get letters
of recommendation from me
and you could still
have my support
in your career aspirations.
OK. That's my promise
and commitment to you.
OK. And the TAs will also
have office hours each week.
Their office hours were
always be on different days
and times than my office hour.
And their office hours are much
more fixed than my office hour.
OK. So, any questions about
anything I've said any
of the announcements so far?
OK. All right.
Textbook, I've already
mentioned this.
Again, it's available on Amazon.
I understand it's sold out.
But you can get it
again from Amazon.
Supplemental text, I'd like you
to have available an organic
chemistry supplemental text.
When I talk about
peptides, for example,
and I talk about amide
bonds, I'm going to assume
that you've read the chapter
on amide bonds and peptides
in this supplemental text, even
if it wasn't covered in 51C.
OK. I'll just ask you to go
back and read that chapter.
OK. And so you need some sort
of supplemental text available
in organic chemistry as
basically as reference.
OK. And it's nice because
this will provide kind
of a lower key treatment
of a more complex topic.
So, for example, if you
want to learn the sort
of the very fundamentals of
DNA or carbohydrate chemistry,
the best place to start is
whatever textbook you use
for 51C.
Now, I realize, many of you
sold your textbook right
after the class was over.
That was a huge mistake.
But it's not too late
to change things.
Number one, I can give you or
loan you a supplemental text
if necessary come
to my office hours.
First five people that show
up will get one of those.
Second, the library--
the science library has
about three shelves that are
like this wide that are filled
with organic chemistry text.
The exact text does not matter.
OK. Basically, if you look
at sophomore organic
chemistry textbooks,
they're all more
or less the same.
OK. What really matters through
is that you have one available
to you that you can
refer to as reference.
You need that for this class,
OK, because I'm going to assume
that you know the
material there.
Now along those lines, I've
gotten a couple of emails
from some of you
who are concerned.
You had trouble with 51C.
You had trouble with
sophomore organic chemistry.
And now you're taking this sort
of advanced organic chemistry
class and you're worried.
OK. Here's what I
want you to do.
First, don't panic.
OK. I will do my best to get
you up to speed on arrow pushing
and some other fundamental
comment--
fundamental principles
in the next two weeks.
OK. So don't panic yet.
At the end of that two weeks,
if what I'm doing on the board
and your ability to keep
up in discussion section
and on the homework or just,
you know, apples and oranges.
You know, fields apart, OK,
you're even on the
same race track,
then you can start panicking.
But for now, no panicking.
OK. If you're really,
really weak in sophomore
organic chemistry, I'd like you
to open the chapters
on carbonyl chemistry.
Whatever books it is,
read the chapter--
re-read the chapters
on carbonyl chemistry
and get up to speed on those.
If you understand how carbonyl
chemist-- how carbonyls react,
how the alpha carbon is
acidic and a few other things,
you'll be fine in this class.
OK. Turns out that's
like 60 or 70 percent
of the organic chemistry
that underlies biology
involves carbonyls.
OK. Start there first.
After you finish with the
carbonyls, come see me again
and I'll get you up-- I'll
give you the next topic
which will probably be amines
or something like that.
OK. Sound good?
OK. So, hopefully I've
allayed some of your fears.
Don't panic yet but get ready
to panic in the next week or so.
And also get ready to
take your game up a notch.
OK. So, that, you know, even
if you have a bad time in 51C,
you can do pretty
well on this class
if you're ready to
work pretty hard.
You know, do lots of problems,
come up with creative
ideas, et cetera.
OK. Discussion sections,
these are mandatory.
This is especially important
if you're weak in
organic chemistry.
Discussion sections
are going to be run
in a problem solving format
and this is your chance to show
that you could do arrow
pushing with the best of them.
So, a lot of the problems in
this class involve mechanisms.
And so, in discussion
sections you'll have a chance
to demonstrate your
ability to do mechanisms.
You'll get up to speed on doing
these correctly, et cetera.
OK. So, again the
first worksheet will be
posted shortly.
The first discussion section
will start this Wednesday,
Mariam will be teaching
that one.
And then after that
it will continue.
OK. Now if you're on a Monday--
if you were scheduled for a
Monday discussion section,
don't panic, what-- the
material that will be covered
on Wednesday well then be
covered on the next Monday.
OK. So, we'll have them slightly
staggered throughout the class.
OK. And it turns that
actually works out fine
because the midterms are on
a Thursday and a Tuesday.
OK. So, there will be two
midterms in this class
and there are no make
up exams available.
They will consist of the
full hour and 20 minutes.
There's going to be an emphasis
on arrow pushing and
concept problems.
There'll be things
like short answer.
There will be no multiple
choice, there's going to be
like short essay type problems.
There'll be problems
where you have
to design experiments,
things like that.
OK. But lots and lots
of arrow pushing,
so get ready for arrow pushing.
In addition, the other
way that I'm going
to assign your grade is I'll be
looking at two written reports
that you're going to
submit in the class.
The first of these is a
journal article report due,
unfortunately, on
Valentines Day.
Happy Valentines Day from
you chemical biology friends.
And in this one, in this
report you're basically going
to be doing the equivalent of a
book report but using an article
from the primary literature
to provide their report.
I've already posted to the
website an example of this.
In addition, instead
of a final exam,
this class will have a
mandatory proposal that's due
on the last day of
class, March 14th.
OK. So, that's a
mandatory proposal,
you can not pass this class
without turning in the proposal.
But there's no final exam.
The proposal will consist
of an original idea
in chemical biology.
Now I know this is daunting.
I've taught this class before.
I know that this is
really intimidating.
Don't panic.
I will have a series of
exercises for you this quarter
that will get you up to the
point where you're ready to come
up with creative novel ideas
in the cutting edge
of chemical biology.
So, you will be ready for this,
you'll be ready to contribute.
And the good news is in
chemical biology there's so much
that we don't know that's
there's lots of room
for smart people
like yourself to come
up with really great new ideas.
And I see this every year,
every year I would take the very
top proposals from this class
and I can present them to the
National Institutes of Health
and they would get funded.
OK. The best ideas I can put
up for faculty ideas anywhere.
OK. So, I've seen that before.
And the other thing is I'm
looking for a small idea.
OK. I'm not looking for, you
know, the next Manhattan Project
or something like that.
I'm just looking for-- just
give me a base hit, you know,
something that will work, that
will teach us something new
about chemical biology.
And you're good.
OK. Quizzes, I will have a
series of quizzes in this class
that will number
between one and five, OK,
more likely to be one to two.
There will definitely be a
quiz sometime in that last week
and the reason is our second
midterm is in February
and the class keeps
going until March.
OK. So, there will
be an easy quiz,
the quizzes in general
are designed to be easy.
They're basically, you
know, recapitulate something
that you just saw on the board.
OK. So, we'll run these either
at the beginning of the class,
at the end of the class
and it'll be something
along the lines
of you just saw this mechanism,
show me again how it works,
OK, something like that.
It just basically
tells me whether
or not you're paying attention
and who's showing up for class.
And by the way I'm
delighted to see all
of you happy people
out this morning.
Welcome. But I know
as the class wears
on that you guys get very busy.
And of course the lectures
will be posted online.
There has to be some incentive
here to get you rolled
out of bed at 9:30
in the morning.
OK. So, we will have
some quizzes.
It won't be too many
and they won't be hard.
OK. That I promise you.
In terms of percent of your
grade, those quizzes only count
for 5 percent the same
level of participation.
Participation counts on both
lecture and discussion and for
that matter even office hours.
OK. So me and Mariam and
Krithika getting to know you,
that's how we determine
the quiz scores--
or the participation scores.
And by the way, I will post
all of these slides online.
OK. So, they'll be all
posted to the website
so you'll have copies of them.
They're not posted now but
they'll be posted shortly.
OK. Each midterm will count for
22 percent of your total grade.
The journal article report
will count for 16 percent.
And then the proposal
which is in place
of the final exam counts for
30 percent of your grade.
OK. So, it's a pretty even
distribution there're lots
of opportunities for you
to get feedback, et cetera.
Any questions so far?
Yeah. And what is your name?
>> Anna.
>> Anna.
[ Inaudible Remark ]
It is. I haven't
talked about that yet.
Thanks for anticipating.
I'll get to that
in just a moment.
OK. Thanks for asking.
And Steve?
No? What is your name?
>> Carl.
>> Carl, OK.
Carl.
[ Inaudible Remark ]
Yeah. No problem.
Carl's question is
what if I'm assigned
to some discussion section that
doesn't fit my schedule, do--
can go to another one?
No problem.
And you can even
go to one one week
and a different one
the next week.
No problem.
OK. And it is posted
online or it's posted
on the syllabus exactly when
the discussion sections will
take place.
Let met show you that.
OK. So, this is the
course website.
OK. Notice over here that
there are instructions
for the book report.
I'll change this very slightly.
For 2013, the instructions
for the proposal,
I'll change this very slightly.
There are three examples
of proposals that got an A
and then the syllabus.
OK. In the syllabus I've
listed the discussion sections
where they meet, et cetera.
Feel free to go to any of these.
OK. Let me zoom through this.
This is online.
I'd like you to read
this carefully.
I'm going to hold you to all of
the provisions that are in here.
OK. So, anything
that's written in here,
it's the equivalent
to me saying it.
All right.
I'm not sure exactly why
it is that's been cut off
in the right.
A lot of this recapitulates
what I've just said.
OK. Let's get to
this, Anna's question.
Over here, there
will be-- let's see.
One moment.
OK. On February 21st,
2013, you will turn
in an abstract for
your proposal.
OK. So, an abstract
is a short condensate
of what your proposal
is going to consist of.
This tells me whether
or not you're on track.
And I'm going to
use this as a way
to give you early
feedback about your idea.
And tell you whether or not
I think your idea fits the
definition of chemical biology.
Whether or not I think
your idea is a creative one
or not so creative.
OK. So, this gives me a chance
to give you feedback before
you turn in your proposal.
OK. And this abstract is
worth 10 percent of the points
for the proposal assignment.
OK. So, in other words 3 percent
of your course grade will be
determined by that abstract.
OK. Note that all
assignments are due
by 11 a.m. on the due day.
There is a late policy.
But I hope that doesn't
apply to you.
Questions so far?
All right.
Yeah? No. Just stretching
all right.
There's some information
here about adds and drops.
There's a frequently
asked questions section.
Do I need to attend
discussion sections?
Yes. Discussing paper,
turning the final assignment.
Oh, if you have not taken
all three quarters of Chem 51
or two semesters of
sophomore organic chemistry.
You should drop the class.
OK. You're going to
blown out of the water.
OK. So, you must
drop the class now.
It's a prerequisite and
then every year someone
slips through.
Don't take this class
if you haven't taken the
full sophomore organic
chemistry series.
OK. OK. There's a whole thing
on incompletes over here.
Academic honesty.
Unfortunately, we're
going to talk
about this later in the class.
I do not want it
to apply to you.
Major portion of your grade is
going to be writing assignments
and so academic integrity
issues loom large unfortunately
in this class.
Every year, I have to
give someone F grade
on the assignment which ends
ups turning into like a C minus,
D plus kind of deal because they
try to plagiarize assignment.
Don't let that be you.
Let's make this the year where
I don't have this problem.
Along those lines,
if this is the year
where I don't have any
plagiarism problems,
I will give an additional
3 percent higher grades.
So, I'll assign the grades
and then I'll go through
and I'll bump up 3 percent
of the course grades
to the next higher grade.
OK. So, if everyone in the class
avoids having any plagiarism
or academic honesty issues.
So no cheating on the
exams, no plagiarism,
no academic honesty I will bump
up the grades by 3 percent.
OK. That means four, five of
you at each level are going
to get a higher grade.
OK. So that means like four
people, three or four people
who are going to get a B plus
I'll move them up to A minus.
I'll take top-- the three
or four top A minuses
and move them up to an A. OK.
That's the deal.
OK. We'll talk some
more about this
because it's a slippery slope
and it's best that we don't have
to have this conversation later.
OK. So, anyway, that's the
information on the syllabus.
I'm holding you entirely to
the contents of that syllabus.
So I'm expecting you to go home
and read the syllabus carefully.
I don't have time to talk
about every aspect of it now.
I'd like you to go home though
and read it carefully please.
OK. Questions?
Questions?
OK. Skip that, skip that.
OK. Let's get started.
So, we already heard
the question,
what is chemical biology?
How does it differ
from biochemistry?
I gave you kind of
a quick answer.
I want to delve into this
topic a little bit further.
OK. So, here's the working
definition of chemical biology
that we'll be using in this
quarter and it's important
that you understands this.
This is the definition is using
chemistry to advance an under--
molecular understanding
of biology
at the level of atoms and bonds.
So, the way I know that
we're talking at the level
of molecular-- at the molecular
level is if we're talking
about atoms and bonds.
OK. And that's what I'm
looking for in terms
of a definition of
chemical biology.
There is a second
corollary to this definition
which is using techniques from
biology to advance chemistry.
And some examples of
these are, for example,
using molecular biology
techniques
to develop combinatorial
libraries of chemicals
which is something that
is one of the projects
that my own laboratory does.
OK. So, there are
two parts of this.
Using techniques from
chemistry to study biology
or using techniques from biology
to solve problems in chemistry.
In both cases, these
involve looking at molecules
at the level of atoms and bonds.
And that's where it's
distinct from biochemistry.
Biochemistry also uses
techniques in chemistry
but oftentimes, they're content
with looking at molecules
as sort of amorphous blobs that
are represented as, you know,
spheres or something
like that in textbooks.
In this class, we'll be down
at the level of atoms and bonds
and that's how you know we'll be
talking about chemical biology.
So, later in the class when I
ask you to come up with an idea
in chemical biology
a proposal idea,
then you should be thinking at
the level of atoms and bonds.
And then that tells you whether
or not your idea
will be acceptable.
OK. So, chemical biology
advances both chemistry
and biology.
And I wanted to give
you a couple
of historical examples to this.
For my money, the very first
chemical biologist was Joseph
Priestley, this guy over here.
He was a remarkable character.
So, he isolated oxygen
and other gases.
OK. So, he was isolating
these using electrolysis
and other techniques.
And he would isolate
these in bell jars
and then he'd use these
chemicals to study biology.
So, one of the experiments
he did
for example was subjecting poor
mice, mice that he would trap
from fields to these different
chemicals that he was isolating.
And he found that the mouse
for example can live in oxygen,
but could not live in
many of the other gasses
that he was isolating.
OK. So that's a really
interesting example
because he's using the very
latest techniques from chemistry
to understand better
how respiration works.
How organisms take in
oxygen and at the same time,
it's using a technique
from biology as a way
of solving a problem
in chemistry.
And the technique in biology
is, does the mouse live or die?
Does the organism-- can
the organism survive
under these conditions
to tell me something
about those chemicals, right.
Joseph Priestley didn't have any
spectroscopy available to him.
So, he is using a
technique from biology,
a very qualitative
technique to be sure
by the method nonetheless
to tell him something
about what's happening
at the chemical level.
OK. Now Sir Joseph-- or Joseph
Priestley had some radical ideas
about colonist in America
and theological descents
that were going on in
England at that time.
And I like to say that the very
first chemical biologist had his
house burned by an angry
mob who came rampaging
through his village
with pitchforks and were
out literally to get his head.
And we had a proud
tradition ever
since of iconoclastic
thinkers and independent people
who were guaranteed
to rile up the masses.
But of course, he's
not getting burned at--
or his house is not
getting burned
because of his chemical virtues.
This was then carried on by Sir
Humphrey Davy who's shown here
at Royal Society of Chemistry
conducting the experiments
on his colleagues.
He's having them
inhale bags made
out of silk that include gasses.
And then he's looking at
the violent excretions
that happened afterwards.
And so, this is just a classic
woodcut from the period.
OK. Now, the other-- so, these
are sort of early workers.
Perhaps historically, the
most important experiment
in chemical biology was done
by the great Friedrich
Wohler in 1828.
Here's a picture of him.
Notice that these
guys are pretty young.
OK. These guys, you know,
they were doing these
stuff in their 20s.
OK. They're not much
older than you.
Any of you in this
classroom five years from now,
you could also be doing stuff
that would change how we
think about the universe.
OK. That's the way
science works.
That's one of the great
things about science.
OK. So, don't think about this
as being done only
by old people.
It's not. It's done-- These
great ideas are often times done
by young iconoclast
who have clever ideas
and just want to
push the balance.
OK. So here's Friedrich
Wohler, 1828,
he is running an
experiment in his laboratory
where he's running this
silver cyanate experiment
where he's trying
to do what would
like just the most pedestrian
of exchanges of salts.
OK. So, what he's trying
to do is synthesize ammonium
cyanate using silver chloride
which he knows will
precipitate out.
Recall from Chem 1
that precipitates
out in a white powder
and he's doing this
by simply mixing silver cyanate
together with ammonium chloride.
And he's expecting
when he heats this
up that the silver chloride
will precipitate out
and he'll be left
with ammonium cyanate.
It turns out that's
not what he got.
OK. That was not the
product that occurred.
Instead, what happened was
he got out this other product
that crystallized out
of the reaction flask.
And when he smelled
this other product,
he knew immediately what it
was, what he smelled was urea.
And urea had been isolated from
urine, from dogs and humans.
And so it was known that
urea is a known compound.
And back then, the primary way
of characterizing the
chemicals was by their smell,
by their taste, you know, some
gross physical properties.
And because urea has
a distinctive smell,
he can readily characterize
this.
Now, here's the significance
of this discovery.
What Friedrich Wohler recognized
was that this urea was identical
to the urea that's attained
from dogs and from humans.
But the difference is this did
not come from a living organism.
In other words, using
just mineral sources,
you can make the same chemicals
that are found in
living organisms.
So, there's not some
sort of special property
that animates the
chemistry of living organisms
that some how makes it special.
Instead, it's going to be
governed by the same rules
that are found in chemistry
that's outside living organisms.
OK. And this is really
important because at that time,
there was this notion
that living organisms would
have some sort of special spark
that in someway would make
them alive and make them--
make their chemistry
unique and special.
And what Wohler is showing
us by this experiment,
is that in fact there was
nothing unique and special
about the chemistry
inside living organisms.
OK. So, these are great
examples of using chemistry
to understand biology
at the level of atoms
and bonds in the case of urea.
Let's move on.
Another principle that underlies
chemical biology is evolution.
We're going to be talking a lot
about evolution in this class.
And so the reason we're going
to be doing this is first,
it simplifies knowledge.
And second, it's going to
guide experimental design.
And here're two views of
the great Charles Darwin.
We can't talk about evolution
without making reference
to Charles Darwin who
articulated in, you know,
150 years ago, much-- you know,
the principles behind evolution.
There are two steps
to evolution.
The first step is to diversify,
to generate a diverse population
of molecules, of organisms,
of phenotypes really.
And then the second step is
to select for the fittest
from this diverse population.
I'll explain the word phenotype
in a moment don't panic
if you didn't understand
that word.
So, there're simply
two steps here.
Select for-- generate
diversity, select for fittest.
These steps are then
repeated again and again
to evolve organisms that can
solve some sort of problem.
In terms of chemical biology,
we think about generating
diverse populations as ways
of shuffling together--
shuffling around biooligomers
in combinatorial manner,
in combinatorial manners.
And I'll show you
that in a moment.
And we often do experiments
that involve some
selection for fitness.
We're going to make a large
population of molecules,
mix them up and pick out
the ones that are most--
that can best fit a criteria
or set of conditions.
This is a very powerful
principle that allows us
to make progress very
quickly in chemical biology.
And this is used as a
technique by hundreds
of laboratories in the field.
OK. So, we use evolution
not just system sort
of theoretical underpinning.
But we also use this as
an experimental framework.
And I encourage you when you're
thinking about proposal ideas,
think about evolution as
a tool to help you speed
up getting towards molecules
that do stuff for you.
OK. So this is used extensively.
Another way that's used
extensively is it's used
to organize knowledge.
When we talk about say the
ribosome, which is the machine
that translates mRNA
into proteins.
And I'll show you what that
looks like in the moment.
I don't have to talk
to you about some sort
of special ribosome that's found
exclusively in humans or dogs
or something like that.
Because it turns out that the
same mechanism used by ribosomes
in humans is also
used by bacteria.
It's even the same mechanism
used by Archaebacteria,
a different stem on the
tree of life entirely.
And so, what this means then is
that, I don't have to teach you
about the special
chemistry of humans.
I can talk about the chemistry
that underlies on all organisms
on the planet because we all
evolved from common ancestors
that solved these mechanistic
problems in chemical biology.
OK. So, this provides
the powerful approach
to evolve molecules
which I alluded
to in the previous slide,
but equally importantly,
this helps us to
organize knowledge
and make it much
simpler for us to talk
about universal chemical
mechanisms
that underlie all
life on the planet.
OK. So, speaking of sort
of universal principles
that underlie all life in
the planet, the Central Dogma
of Modern Biology is use--
is going to appear in multiple
ways throughout this quarter.
In the first way, this is how
we've organized the textbook
that we'll be using
this quarter.
OK. So, the textbook
has different chapters.
And it's organized according
to the Central Dogma.
So, the Central Dogma
describes all biosynthesis
that takes place in
cells and on the planet.
OK. So, everything that
you're going to synthesize
in your cells is in some way
encoded by this Central Dogma.
The Central Dogma tells us
that the DNA found in nuclei
in eukaryotic cells
is the blueprint upon
which all biosynthesis is based.
This DNA is transcribed into RNA
and then translated
into proteins.
OK. So, this is the
earliest diagram
by the Great Francis Crick
who recognized the far reaching
implications on this Dogma.
Very early on, OK, this
is his earliest example
of where it was articulated.
It looked just like this.
We know now, for example,
that there is in fact--
this dash line over here
is in fact a real line.
There is an enzyme
reverse transcriptase
that can convert RNA into DNA.
But this line over here
where RNA is used a template
to make new copies of it self,
this line never materialize.
We have not found it in
many years of looking.
In fact it would be a great
chemical biology proposal
to come up of the
way of doing that.
OK. So here's a different
way of looking
at the Central Dogma
of Modern Biology.
So, at the very top, DNA, this
biopolymer up here is going
to encode messenger RNA
and in fact all RNAs.
This-- The conversion of DNA
into the complimentary RNA takes
place using an enzyme called
RNA polymerase.
OK. This is nice
because it's going
to be polymerizing
RNA, this make sense.
I'm going to be referring
to enzymes today
and in future classes,
enzymes are proteins
that catalyze chemical
transformations.
OK. So, these lower the
transition state energy
for key reactions that
take place in the cell.
And here's our first
example of this.
The enzyme RNA polymerase that's
responsible for transcription.
In addition, there's an
enzyme DNA polymerase
that allows replication of
the DNA to make new copies
of the DNA when the
cell has to divide.
OK. Here's the ribosome
that I alluded to earlier
on a previous slide
that is responsible
for translation of
RNA into proteins.
This Central Dogma continues
as proteins then can
catalyze reactions that lead
to other biooligomers
that are going
to be very important
in this class.
For example, we're
going to see a class
of biooligomers called
terpenes that are used in--
used by plants and
microorganisms for signaling.
Polyketides, a class of
molecules that's very important
as natural products
for antibiotics
and other pharmaceutical uses.
And then oligosaccharides,
the glycans that decorate
the surfaces of your cells
and play key roles in
protein folding and key roles
in cell base signaling.
OK. So, here's my
plan for this quarter.
We're going to have
two lectures about each
of the biooligomers
that's depicted here.
OK. So, next week, I'll talk two
lectures about arrow pushing.
Week three, we'll have
two lectures about DNA.
Week four, two lectures
about RNA.
Week five, two lectures
about proteins.
Week six, oligosaccharides.
Week seven, polyketides.
Eight is terpenes.
Oh, actually, I'm sorry.
I'll have four lectures
total about proteins.
I can't resist.
I'm a protein guy.
So, yeah, so we'll have a total
of four lectures about proteins,
but everything else we'll
have two lectures about.
And we'll be covering a
chapter a week in the class.
OK. So, necessarily
some of the material
of the textbook will
be left aside.
OK. Everyone still
with me so far?
>> Yes.
>> OK. So I told you that
everything that synthesized
in the cell is synthesized
in a deterministic way,
starting with the DNA up here.
And it turns out that's not
strictly, strictly true.
And I want to explore
a little bit more
about what the subtleties
of this concept.
So, first of all, we need
to define what is the
unit of synthesis?
So, proteins and DNA, oh sorry,
DNA is read out in
units called genes, OK,
where each gene is going
to coat a single protein.
Genes have two essential
parts, an on-off switch
and an express sequence.
The on-off switch is where
transcription factors bind.
These are proteins that can
encourage RNA polymerase to bind
to the start of this
gene and encourage it
to start transcription.
OK. Similarly there's
other-- if there's promoters,
there's also other ways
of shutting off the
synthesis as well.
It gets complicated.
This transcribe region then
becomes the messenger RNA
which is then translated
by the ribosome
into the protein down here.
OK. So, here is an example
for a transcription
factor binding to DNA.
Notice that the DNA
has a structure
that can nicely accommodate
the structure of this protein.
I'm going to be talking a lot
more about proteins later.
But I want to tell
you about a convention
that we're going to be using.
OK. So, proteins hopefully
as you know are composed
of amino acids that are strung
together by amide bonds.
OK. If what I told you totally
doesn't make sense, read--
go back and read the
reference supplemental organic
chemistry text.
OK. So, when we look at these
amino acids and we just look
at the amide bonds and
the carbon that's alpha
to that amide bond.
We can trace out that back bone
using these ribbon structures.
So, these ribbon structures
do not look at the side chain
of amino acid, rather they
simply trace out the sort
of the scaffolding back
bone of the protein.
OK. So, that's what these
ribbon diagrams will look like.
And then here's a
structure of DNA down here.
Notice that this alpha
helical ribbon, this curly,
cute ribbon fits neatly
into the DNA's major grove.
We'll talk much more
about that later.
OK. Let's take a look at
the world's smallest gene.
This is the Guinness Book of
World Records for smallest gene.
In this case, this gene encodes
for microcin C7 or the gene--
the protein it will encode
for is called microcin.
Microcin is a translation
inhibitor.
It's a protein.
It's-- Well, it's a peptide,
short piece of protein
called a peptide that's used
by microorganisms to
kill off their neighbors.
OK. So, the microorganisms
that grow in your skin,
that grow in the, you know,
far recesses of this--
of the walls, you
know, that grow all
around you are constantly
fighting chemical warfare
with each other.
OK. Their goals are to
kill off their neighbors
and then give themselves more
resources that allow them
to grow better, OK, to grow
faster and to be more populous.
OK. And microcin is
a good example of one
of those antibiotics
or compounds
that kill other organisms.
OK. And this is actually a
very complicated binary toxin.
On the one hand, there's
this peptide over here
that allows the microcin
to be transported
into the competing bacteria.
OK. So, the bacteria, look
at this complicated thing,
they sniff at the peptide
region and think, "Oh,
that peptide looks yummy.
And if I eat that, I'll
get amino acids as a source
of building blocks
for my own proteins."
OK. That's kind of
like the bait.
OK. So, the competitor
picks up the bait,
transports microcin into--
the microcin c7 into it--
into itself and in which case,
enzymes in the competitor then
break a part this peptide.
And then unveil the translation
inhibitor down here that shuts
down translation
by the ribosome.
This is very bad news for
the competitor, right?
If the competitor organism--
microorganism can not
translate mRNA into proteins,
it cannot live, it
cannot divide,
it will die very quickly.
OK.
And so, in the end,
what we're seeing is
that the smallest gene
is rather complex.
Its toxic fragment is
highlighted over here
and the rest of it also
plays a key role as well.
OK. So, this-- to make
something as complicated
as this requires a large
number of genes that are lined
up over here where each one
of these arrows represents
a sequence of DNA.
OK. And we'll talk more
about the directionality
of the arrows, you
know, later, week three.
For now don't get too
worked up about it.
Notice though that it
takes several genes
to compose this toxin.
OK. So, some of these genes
are doing things like adding
on this non-peptide
like toxic fragment.
OK. So, some of these genes
up here are encoding
various enzymes.
OK. So that's this microcin,
this mccB, mccD, mccE enzymes.
So these enzymes are adding on
stuff and modifying the peptide
that was otherwise encoded by
mccC in the center over here.
OK. I'm sorry, mccA that
was encoded up here.
Now, at the end of this,
even though this is
the world's smallest--
you know, smallest
gene delivering a tiny
little peptide.
The resulting peptide is
still fiendishly complex.
OK. This thing includes
a large number
of different stereocenters
indicated
by the dashes and the wedges.
And furthermore, this isn't
the half of it, right.
This is just very
simple example.
The proteins we'll
be talking about,
the proteins I've been
showing you today, for example,
the transcription factor,
consist of hundreds of subunits,
hundreds of amino
acids, each one likely
with its own stereocenter.
And so the chemical biology
considerations become enormous
when we start looking at
this in greater detail.
OK. All right.
So, we've looked at a
gene let's talk next
about the collection of genes.
All of the genes
together that are found
in an organism are
referred to as a genome.
Here's one representation
of the genome
of the bacteria model system,
bacteria called E. coli.
We'll be talking a
lot about E. coli.
I'll have another slide
about it in a moment.
This is used extensively
in chemical biology
laboratories including mine.
And its genome looks like this.
Where in this representation
it's shown as a circle
and each one on these colored
bars tells us something
about the size of the
gene, whether not it's GC--
whether it's GC richness
is, et cetera.
OK. So, reading out
the information here,
not so important.
Suffice it to say that
the human genome has
around 24,000 or so genes.
And when you compare that
against almost any other machine
that we have around us,
this number sounds
ridiculously small.
One of the challenges, however,
is even though we have
this complete parts list
for a simple organisms
like E. coli,
it's not clear what each
one of these parts is doing.
And so a goal of functional
genomics and a goal
for that matter of
chemical biology is to try
to make better sense
of this parts list.
OK. And let me show you what
I mean on the next slide.
OK. Let's imagine that you
had a transmission from a car.
OK. And imagine that
you had parts list
of all the different gears
found in that transmission.
OK. I could tell from some
experience that just starring
at those different gears, even,
you know, starring as hard
as you possibly can and
using your best, you know,
sort of logical reasoning,
you're going to have really,
really hard time trying
to put together each one
of those little gears.
OK. I don't care
how smart you are.
It's a really hard problem.
And so, we have that same
problem when we look at genomes.
When we look at genomes,
it's not clear what each one
of these parts are doing.
And one of the roles
of chemical biology is
to help us annotate genomes and
teach us about what each one
of those parts is doing in
terms of the larger machine.
We'll talk some more about that.
There'll be a topic
called Functional Genomics.
OK. So chemical biology
helps us fill in the dynamics
of the process and how
these pieces fit together.
OK. So, one way that
it fills in dynamics,
dynamics means change
overtime is an important area
of chemical biology develops
new tools that allow us
to see molecules at the
single molecule level
and understand how
they change overtime.
How they dynamically
interconvert it
to different speeds
and things like that.
And Mariam is one of the
world's experts at this.
She can tell you
more about this.
Now, another big
challenge that we have is
that often times we have
big differences in genomes
that lead to the same species.
Here for example are
three different strains
of the model bacteria, E. coli.
OK. So, here're three different
strains and only 40 percent
of proteins are shared
between these three.
Notice that they look identical,
they're all the same species
because they can mate, they can
exchange DNA with each other
which in terms of bacteria turns
out is not necessary the same
as being same species.
But in any case, these are
named-- all named E. coli,
yet they have vast differences
in what DNA they've picked
up from their environment and
from other microorganisms.
So, simply knowing the parts
list is not going to be enough
for us to explain what's
similar and different
between these organisms.
OK. And for that matter when
we start looking at different--
when we start looking
at different organisms
from the same population,
we see a similar sort
of diversity despite
having very,
very, very similar genomes.
OK. So, I've been
talking to you both
about humans and also bacteria.
I need to hopefully just
very briefly review for you
that the differences in
those organisms are vast.
OK. I'm hopefully not
telling you anything you don't
already know.
Bacteria are classified
as prokaryotes,
humans and other multi-celled
organisms or organisms even
that are single cell that
have multiple compartments
in them are classified
as eukaryotes.
I'd like you to or I'll
tell you that in a moment.
The big difference here is
that the prokaryotes don't
have any compartments
for the most part.
The DNA has kind of
organized into nucleoid,
but for the most part there are
no compartments in the inside
of the cell of a prokaryote.
Whereas when we look at
eukaryotes under the microscope,
we find something
totally different.
What we find is a
bunch of organelles
which are these little
compartments in here.
OK. And these organelles
have different functions
for the cell rather than being
just the big bag that has all
of the functions
being carried out kind
of randomly within that bag.
OK. Now, getting back
to this idea of genomes,
nearly identical genomes can
lead to very different people.
So, even though our genomes are
99.9 percent identical we see
vast differences.
So, this is a challenging
concept
but what's happening
here are vast differences
in transcription underlie
these different phenotypes
that are observed
where phenotype is the
physical outcome of the gene.
OK. So all of us have
roughly the same genomes,
yet the phenotypes that come
out differ at the cellular level
by different transcription
levels that program our cells
into having different functions.
So, even though each one of
these cells has the same genome
that cells end up having
different functions
by having different
transcription levels
of different sections
of the gene--
different genes within
the genome.
And furthermore at the
organismal level this plays
out in other ways as well, OK,
also at the level
of transcription.
OK. So, here're six
different human cells
and you can see vast differences
in their morphologies,
their shapes, et cetera.
And for that matter, I don't
think I have to work hard
to convince you that these have
very different functions inside
the organism, in
this case humans.
OK. So, I showed you briefly
a prokaryotic cell over here,
I'd like you to memorize
all of the structures.
Everything that's labeled
here and labeled in the book--
the textbook, OK, you should
memorize the structures.
And along those same
lines I'd like you
to memorize all the
parts that are labeled
in the textbook for
eukaryotic cell.
OK. So you should know basically
the simple anatomy of a cell.
OK.
>> Do you know its
functions as well?
>> The basic functions.
If it's in the book,
yeah, I like you to know.
OK. So, we've looked at DNA.
DNA gives us genes,
which gives us genomes.
Next section down on the
Central Dogma is RNA.
So, from RNA the complete
collection of RNA transcripts
in a cell tissue organism
is called the transcriptome.
OK. So here's the DNA, the
genome of the organism.
Here's a bunch of RNA
transcripts and the number
of copies that each one of
these transcripts is controlled
by transcription factors
that I showed you earlier.
OK.
That was the alpha helix
fitting into the DNA.
If that transcription factor
is very effective at grabbing
on to RNA polymerase then
you'll get more copies
of the mRNA transcript
being produced.
OK. So these more copies
of the transcript being
produced can give rise
to very different
phenotypes of the organism.
So ultimately a lot
of the phenotypes
that observed are being driven
by differences in transcription,
in addition to differences
in the encoding DNA.
Everyone still with me?
OK. Things are going to
get a little bizarre next.
It turns out that the
RNA that's encoded
by DNA is further diversified by
a process called RNA splicing.
OK. So RNA splicing takes the
RNA that's encoded by the DNA
and then sort of shuffles
it around very subtly.
OK. And the results are a bunch
of different mRNAs encoding
potentially different proteins
down here.
OK. And the results sometimes
are dramatically differences
in the result in proteins.
So these proteins,
the consequences
in this can be proteins that
have very different function
from the starting mRNAs.
You can end up with two
different proteins splice
variance of each other that
are encoded by the same DNA
that have different
results inside the cell
in different phenotypes.
OK. Now there's going
to be further diversity
but just to organize things.
So we've seen at the DNA
level, the collection
of all genes is called
the genome.
We've seen at the RNA
level, the collection
of all RNA transcripts is called
the transcriptome and then
at the level of proteins,
the collection
of all proteins is
called the proteome.
OK. This is-- There is a sort
of a neat organization
to all of this.
OK. Now what I'm showing you,
I've already showed
you this representation
of the genome for E. coli.
This is a way of representing
the transcriptome using a
technique called
RNA microarrays.
We'll talk about this
more in week four.
And then you can do a similar
thing that make a big collection
of all the different proteins
found in the cell of organism
or tissue and array these on
microscopic slides as well.
OK. So, all these techniques
are ones that we'll talk
about later in the class.
OK. So we've talked
about how you can start
with an RNA transcript.
Oh, question over here.
>> I just wonder what
the RNA splicing--
>> Yes.
>> -- for the message RNA.
[ Inaudible Remark ]
>> OK. So what is your name?
>> Ashley.
>> Ashley.
OK. So Ashley's question is
what actually gets translated
on the messenger RNA?
>> Yes.
>> And--
[ Inaudible Remark ]
And there's what?
>> In translating the mRNA.
>> Yes, what actually gets
translated into proteins
from the messenger RNA?
OK. That's your question right?
>> No.
>> No.
[ Inaudible Remark ]
Yes.
[ Inaudible Remark ]
The axons?
[ Inaudible Remark ]
Oh, OK. So your question
is more subtle than that.
OK. So could I defer
that until we get
to week four which is the RNA?
>> OK, yeah.
>> OK. Good question.
We'll get an answer.
Other questions?
OK. So we've seen how splicing
can start with transcripts
and then add additional
diversity.
It turns out that
proteins are also subject
to diversification as well.
So after the proteins
are synthesized
by the ribosome during
translation, these are subject
to further diversity in a
couple of different ways.
OK. The first way
is for the proteins
to be modified chemically
on their surface,
and so one example of this
is an elongation factor II.
So this is posttranslationally
modified
to produce this functionality
up here called diphthamide.
OK. So the protein is
enzymatically converted
from having this imidazole
functionality up here
into having a diphthamide
functionality.
This is absolutely required for
translation by this organism,
organism being humans.
OK. So elongation factor II
that's been posttranslationally
modified is required for
translation to take place.
However, the diphtheria
toxin has a way
of cleaving off this
diphthamide.
OK. When that happens,
that prevents protein
translation from taking place.
OK. Diphtheria toxin
fascinating,
it's an effective
way of killing cells.
What's important here though
is this notion that even
after the proteins
are synthesized,
they're further diversified
by chemical reactions
that take place on
their surface.
Because this takes place after
translation, these are referred
to as posttranslational
modifications.
OK. Post meaning after;
translation, modifications.
Translational modifications.
And this is really important.
This means that we can start,
let's say, 24,000 or so genes
in the genome get,
you know, say 50,000
or 60,000 different
splice variance,
get say 60,000 different
proteins
and then further diversify
those 60,000 different proteins
into to 200 or even more
thousand different proteins.
So in the end although our
genomes look relatively
uncomplexed at the level of
24,000 or so different parts,
the true number-- this vastly
understates the true number
of parts which is
much, much larger due
to reactions like this one.
OK. Furthermore,
these proteins go off
and catalyze other functions
within the cell leading
to further diversity.
OK. Everyone still with me
in the posttranslational
modification?
Let me show you what I mean.
I refer to this as
posttranslational processes.
So, this is the process by which
proteins catalyze as enzymes,
the production of other
molecules, oligosaccharides,
glycans, polyketides
and terpenes.
OK. So, once the enzyme is
made, it's just the start.
After that, all kinds of
other things take place.
OK. And this is-- proteins
can be covalently altered
by enzymes.
OK. That's the modified
proteins that I showed you
on the previous slide.
In addition, there are
spontaneous processes
that alter the surfaces
of proteins.
OK. So, for example,
oxidation of proteins is sort
of an unavoidable consequence
of having a metabolism that's
dependent upon oxidation, right,
and producing oxidation
products.
So, there are some
strong oxidants
that are produced by your cells.
And those oxidants will come
along and modify the surfaces
of proteins, spontaneously, OK,
using thermodynamically
accessible reactions.
And so these are examples of
posttranslational modifications.
In addition, proteins themselves
will catalyze reactions
that will synthesize
these molecules down here
which again are part
of the Central Dogma,
their biooligomers.
Now, one thing I have to tell
you is that while I told you
that the Central Dogma
in a deterministic way
determines everything that's
been synthesize by the cell--
while it determines everything
synthesize by the cell,
it's not purely deterministic.
OK. And there's an element
of randomness to all of this.
OK. And that's what I want
to show in the next slide.
OK. This is-- we're going to
have randomness in the sense
that the Central Dogma will
dictate the identity of enzymes
and then these enzymes are going
to go up and catalyze reactions
that will not be
determined by the DNA.
That will be at some level
a little bit randomized.
OK. So, one good example
of this is the process
of appending oligosaccharides
to the surfaces of proteins.
OK. So, R over here is meant to
represent a protein and each one
of these shapes is meant
to represent a different
carbohydrate, glycan,
that's being-- that's
going to be attached
to the surface of the protein.
OK. Now, the way this
works is that each one
of the enzymes that's going to
do this attachment is encoded
by some gene up here, encoded
by the DNA, translated--
transcribed into messenger RNA
which in turn makes the protein,
the enzyme that's going
to catalyze bond formation
to add this glycan onto
the oligosaccharide.
OK. What's less clear though
is, you know, small variations
in the resulting
glycans down here.
So, for example, enzyme
2 makes this bond,
if there's enough enzyme 2
around maybe it makes
another bond.
Enzyme 11 makes this bond,
but maybe if there's
enough enzyme 11
around maybe it makes
another bond over here.
So, there's diversity in
the resulting structures
that are biosynthesized
by the enzymes.
OK. Furthermore, even though
I'm lining up the enzymes
in this order, the order of the
genes in the genome is unrelated
to the final product that
results in this glycan
on the surface of the protein
which eventually appears
in the surface of the cell.
So, there is considerable
heterogeneity
in these posttranslational
processes.
Both in terms of modifications
in the sense that some
of these modifications are
occurring spontaneously just
through thermodynamically
accessible reactions.
And furthermore, when these
posttranslational processes are
catalyzed by enzymes, there
is considerable stochasm,
randomness in terms of what the
resulting structures will be.
OK. So this is one of these
kind of mind-blowing concepts
that we have to get
comfortable with.
OK. That we can't
in a deterministic way
know every single molecule
in a cell to a precise level.
OK. Everyone comfortable
with that concept?
OK. Don't look so
moppy-eyed and downcast.
At the end of this
class, hopefully,
you'll at least have a
framework to understand it, OK.
OK. So, I want to
switch gears now and talk
about some other principles,
different types of techniques
that you need to know that
are going to make our lives
so much easier in understanding
the experiments behind
chemical biology.
OK. So earlier, I told you
that an important principle
in chemical biology
or an important technique
used extensively
in chemical biology is
to make large diversity,
a large diversity of
molecules, and then sift
through this diversity
to find a few molecules
that do something special.
OK. This is a technique
of molecular evolution.
It's used extensively
in chemical biology.
So, there's going to be one
equation in today's lecture
that I need you to know.
And this is the equation
that determines the diversity
of a collection of molecules.
That diversity, the
number of oligomers
that results is the number of
subunits raised to the power
of the length of the oligomer.
OK. And let me try to
show you this in action.
OK. So, let me turn
on some lights here.
OK. So let's start with DNA.
Let's make a big
collection of DNA.
So, DNA consist of four bases,
OK, A, C, G, and T. Again,
we'll talk some more about their
chemical structure in a moment.
Let's try to imagine then that
we're going to make a collection
of all possible tetramers.
OK. OK. Number of possible DNA.
Let's make it pentamers.
OK. OK. So the number of
possible pentamers is going
to be equal to the
number of subunits raised
to the length of
the biooligomer.
OK. So, this-- the number
of sub units is four,
that's the number of bases.
The-- Raised to the
power of 5 that's
because we're making pentamers.
OK. If we wanted to make-- OK,
so this is example of five-mers.
If we want to do
ten-mers, again,
we'd have 4 raise
to the 10th power.
OK. OK. So this is a very simple
equation, very, very useful.
It can tell you very
rapidly whether
or not the experiment you've
proposed is reasonable, right.
If you propose something,
that's going to fill this room
with DNA probably not
so reasonable, right.
That's not practical.
But if you propose something
that you could fit and say,
a 1 ml test tube, totally
reasonable, or 1 ml tube,
[inaudible] tube,
that would work.
OK. OK. Any questions
about this formula?
You ready to apply it?
OK. Good. OK.
One of the great feelings
of teaching a class
like this one is that the
example problems that I'll do
for you where we applied
equation or whatever,
inevitably are a lot
easier than the ones
that appear on the exam.
And I apologize about that.
That's kind of-- that's
part of pedagogy I guess.
OK. Now, it turns out that
chemical biologists apply this
to DNA, but they also apply it
to much more complicated
molecules.
So for example, we can do
a combinatorial synthesis
of a series of molecules
that look like this.
OK. So, we could do, we can
setup a modular architecture
to allow combinatorial
synthesis that in a way similar
to composing biooligomers
will result in molecules
that have modules that have
been tethered together.
OK. So for example, this is--
this is a framework
called the peptoid.
OK. And so instead of a peptide
where the peptide would
have a side chain coming
out on the alpha
carbon over here.
Instead this had side chains
coming out on the nitrogens.
You can very readily make a
large combinatorial library
of these peptoids and
make a great diversity
of number structures using
exactly the same formula
that I showed on
the previous slide
to calculate the
result in diversity.
OK. And let me show
you how that work.
If you have 20 subunits,
so you have 20 different
possible building blocks,
and you're going
to make three-mers,
then you would have
20 to the power of 3,
20 raised to the third
power would be the result
in diversity of that library.
OK. Where a library is a
collection of diverse molecules.
OK. So, this idea
of combinatorial diversity
applies both at the level
of shuffling around biooligomers
and is applied in biology.
But equally importantly
it's used as a principle
that underlies chemical
synthesis in chemical biology
as well, including
the chemical synthesis
that you learned
about back in 51C.
OK. And we can get much more
complicated and make libraries
of benzodiazepines
which are shown here.
And this is an important class
of small molecules
that's very commonly use
in many different drugs.
OK. Why don't we stop here?
When we come back next
time, we'll be talking
about diversity of biology.
[ Silence ]
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