Seminar Presentation - Ligand Residence Times and Exit Pathways Obtained in Silico without Biasing Forces

CMSE Professor Alex Dickson 

Ligand residence times and exit pathways obtained in silico without biasing forces

Department of Pharmacology and Toxicology Seminar

DATE: Friday February 19, 2016

TIME: 9:00am – 10:00am

LOCATION: B448 Life Science

Kinetics, in addition to thermodynamics, can be an important tool in drug design. The mean residence time that a ligand spends bound to its binding pocket, has been shown to be more predictive for efficacy than the binding free energy. In addition, differences in binding kinetics can also be leveraged in designing selective ligands for substrates with different lifetimes in the cell. However, while free energies can be obtained using end-
point methods such as free energy perturbation, kinetic information is sensitive to details  of the (un)binding pathway, specifically the probability of the transition state. Using a recently developed enhanced sampling for molecular dynamics (WExplore) it is possible to efficiently obtain residence times that agree with those determined experimentally, and determine structural details of the transition state that governs binding kinetics. The  method is based on unbiased trajectory segments, and is amenable to the generation of Markov State Models and network visualizations that show the ensemble of binding and unbinding pathways, and allow for the calculation of the entropy of the transition state ensemble.