Past Event: Exploring Fitness and Free Energy Landscapes of Proteins, Two Short Stories

Please join Yale Chemistry for a Silliman Seminar in Theoretical Chemistry with Prof. Ronald Levy, Director of the Center for Biophysics and Computational Biology and Professor of Chemistry, Physics, and Biology, from Temple University.

Summary: I will present two short stories that review our recent work using sequence-covariation Potts statistical energy potentials and MD free energy simulations in an integrated way to explore the fitness and conformational free energy landscapes of proteins. The first story is focused on Kinase Family Proteins. Inactive conformations of protein kinase catalytic domains where the DFG motif has a “DFG-out” orientation and the activation loop is folded present a druggable binding pocket that is targeted by FDA-approved ‘type-II inhibitors’ in the treatment of cancer. Tyrosine Kinases (TKs) typically show strong binding affinity with a wide spectrum of these inhibitors while serine/threonine kinases (STKs) usually bind more weakly. We propose that this difference is due to evolutionary divergence in the conformational landscapes of TKs vs. STKs. Potts statistical energy analysis together with mutational scanning using MD free energy methods suggest a molecular rationale for our observations which I will describe. The second story is focused on drug resistance in human immunodeficiency virus (HIV), an increasingly pervasive problem that affects the lives of millions of people worldwide. Epistasis, the interactions between a drug resistance mutation (DRM) and other residues in HIV protein sequences, is suggested to be key to these dynamics. My talk will describe how we use a Potts sequence-covariation statistical-energy model of HIV protein fitness under drug selection pressure which captures epistasis between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the temporal acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences.

For more information on Professor Levy's research: https://ronlevygroup.cst.temple.edu/levygroup_research.html.

Faculty Hosts: Professor Tianyu Zhu and Professor Bill Jorgensen.

This seminar is generously sponsored by the Mrs. Hepsa Ely Silliman Memorial Fund.

Location: Sterling Chemistry Laboratory (SCL), Room 160

This seminar can be viewed online here: Panopto