Lane W Votapka, Anupam Anand Ojha, Naoya Asada, Rommie E Amaro
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Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics.
Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here, we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times. Using the pharmaceutically relevant threonine-tyrosine kinase (TTK) and eight long-residence-time (tens of seconds to hours) inhibitors, we demonstrate accurate prediction of absolute and rank-ordered ligand residence times and free energies of binding.
期刊介绍:
The Journal of Physical Chemistry (JPC) Letters is devoted to reporting new and original experimental and theoretical basic research of interest to physical chemists, biophysical chemists, chemical physicists, physicists, material scientists, and engineers. An important criterion for acceptance is that the paper reports a significant scientific advance and/or physical insight such that rapid publication is essential. Two issues of JPC Letters are published each month.