Biology subjects

Peter Wolynes

Publications and source records attributed to Peter Wolynes.

3 recordsLinked to original sources

bioRxiv2016

Stochastic dynamics of genetic broadcasting networks

The complex genetic programs of eukaryotic cells are often regulated by key transcription factors occupying or clearing out of a large number of genomic locations. Orchestrating the residence times of these factors is therefore important for the well organized functioning of a large network. The classic models of genetic switches sidestep this timing issue by assuming the binding of transcription factors to be governed entirely by thermodynamic protein-DNA affinities. Here we show that relying on passive thermodynamics and random release times can lead to a \"time-scale crisis\" of master genes that broadcast their signals to large number of binding sites. We demonstrate that this \"time-scale crisis\" can be resolved by actively regulating residence times through molecular stripping. We illustrate these ideas by studying the stochastic dynamics of the genetic network of the central eukaryotic master regulator NF{kappa}B which broadcasts its signals to many downstream genes that regulate immune response, apoptosis etc.

Systems Biology↗

bioRxiv2015

Shape Transitions and Chiral Symmetry Breaking in the Energy Landscape of the Mitotic Chromosome

We derive an unbiased information theoretic energy landscape for chromosomes at metaphase using a maximum entropy approach that accurately reproduces the details of the experimentally measured pair-wise contact probabilities between genomic loci. Dynamical simulations using this landscape lead to cylindrical, helically twisted structures reflecting liquid crystalline order. These structures are similar to those arising from a generic ideal homogenized chromosome energy landscape. The helical twist can be either right or left handed so chiral symmetry is broken spontaneously. The ideal chromosome landscape when augmented by interactions like those leading to topologically associating domain (TAD) formation in the interphase chromosome reproduces these behaviors. The phase diagram of this landscape shows the helical fiber order and the cylindrical shape persist at temperatures above the onset of chiral symmetry breaking which is limited by the TAD interaction strength.

Biophysics↗

bioRxiv2015

Molecular stripping in the NFκB/IκB/DNA genetic regulatory network

Genetic switches based on the NF{kappa}B/I{kappa}B/DNA system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that I{kappa}B can actively remove NF{kappa}B bound to its genetic sites via a process called \"molecular stripping\". This allows the NF{kappa}B/I{kappa}B/DNA switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor NF{kappa}B and its various binary and ternary complexes with DNA and the inhibitor I{kappa}B. These studies show that the function of the NF{kappa}B/I{kappa}B/DNA genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of I{kappa}B which occurs through conformational selection. Free energy calculations for DNA binding show that the binding of I{kappa}B not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

Biophysics↗