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 the structural details of the transition state that govern binding kinetics. The method is based on unbiased trajectory segments, and is amenable to the generation of Markov State Models and network visualization that can show the ensemble of binding and unbinding pathways, and allow for the calculation of the entropy of the transition state ensemble.

Enhanced sampling of ligand binding: Pathways and kinetics

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.