Download Coarse-Graining of Macromolecules

Lecture 3: Statistical Mechanics of
Gene Regulation
(Small et al.)
(Schulten et al.)
Rob Phillips
California Institute of Technology
How Big is a Genome?
“The Great Polymer Languages”
A Reminder on DNA: One of the “Great
Polymer Languages”
The Meaning of a Terabyte
1 gggcggcgac ctcgcgggtt ttcgctattt atgaaaattt tccggtttaa ggcgtttccg
61 ttcttcttcg tcataactta atgtttttat ttaaaatacc ctctgaaaag aaaggaaacg
121 acaggtgctg aaagcgaggc tttttggcct ctgtcgtttc ctttctctgt ttttgtccgt
181 ggaatgaaca atggaagtca acaaaaagca gctggctgac attttcggtg cgagtatccg
241 taccattcag aactggcagg aacagggaat gcccgttctg cgaggcggtg gcaagggtaa
301 tgaggtgctt tatgactctg ccgccgtcat aaaatggtat gccgaaaggg atgctgaaat
361 tgagaacgaa aagctgcgcc gggaggttga agaactgcgg caggccagcg aggcagatct
421 ccagccagga actattgagt acgaacgcca tcgacttacg cgtgcgcagg ccgacgcaca
481 ggaactgaag aatgccagag actccgctga agtggtggaa accgcattct gtactttcgt
541 gctgtcgcgg atcgcaggtg aaattgccag tattctcgac gggctccccc tgtcggtgca
601 gcggcgtttt ccggaactgg aaaaccgaca tgttgatttc ctgaaacggg atatcatcaa
………………….
48301 catgaggttg ccccgtattc agtgtcgctg atttgtattg tctgaagttg tttttacgtt
48361 aagttgatgc agatcaatta atacgatacc tgcgtcataa ttgattattt gacgtggttt
48421 gatggcctcc acgcacgttg tgatatgtag atgataatca ttatcacttt acgggtcctt
48481 tccggtgatc cgacaggtta cg
(Thanks to Farid Abraham)
Sizing up E. Coli
A Reminder on the Central Dogma
Lifestyles of Bacteriophage
Gene Regulatory Decisions: The
Case of Phage Lambda
Phage lambda can either
lay in wait or immediately
reproduce.
Viral life cycle dictated by
regulatory decisions – the
lambda switch.
Gene Regulation and
Development: Case of Drosophila
Spatial patterns of gene
expression lead to anteriorposterior polarity.
Gradients in regulatory
proteins.
(Berman et al.)
The Great Idea of Jacob and
Monod: Genes that Control Genes
Observations on phage life
cycle and bacterial growth
in presence of different
sugars led to picture of
gene regulation.
Use of sugars other than
glucose (such as lactose)
seemed to be tightly
controlled.
(Muller-Hill)
How Are Genes Regulated?
Genes can be regulated at
many stages along the
path from DNA to protein.
Transcriptional control is
one of the most important
mechanisms and will be
the focus of our
discussion.
RNA Polymerase: Bound or Not?
For us, the whole question of transcriptional regulation will come down to the
question of whether or not RNAP is bound to the promoter or not!
There are an array of molecules (transcription factors) that participate in
recruiting RNAP to its promoter.
(Ptashne and Gann)
(Cramer ‘02)
Repressors: The Cartoon
Repressor molecules inhibit
action of RNA polymerase.
Repressors can be under the
control of other molecules (i.e.
inducers) that dictate when
repressor is bound and not.
Activators: The Cartoon
Activator molecules enhance the
action of RNA polymerase.
Activators can be under the
control of other molecules (i.e.
inducers) that dictate when
activator is bound and not.
Activators “RECRUIT” the
polymerase.
Adhesive interaction between RNAP
and activator
All Together Now: The Lac Operon
Our goal: mathematize
the story told by all of
these cartoons.
In particular, compute
the probability of RNAP
binding as a function of
concentration of all the
other molecular actors.
Structures of the Molecular Actors
in the Lac Drama
Lac Repressor
RNAP+DNA+mRNA
Products of the Lac Operon
CRP and DNA
(Beautiful work of David Goodsell)
Repression in the Lac Operon: the
Role of Looping
pbound ( L  0)
Repression (L) 
pbound ( L)
Repression level depends upon the spacing of
the operators.
Once again, we assert that the dynamical
definition can be replaced by an equilibrium
description.