Prediction of Threonine-Tyrosine Kinase Receptor-LigandUnbinding Kinetics with Multiscale Milestoning andMetadynamics

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. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/606239v1_ufig1.gif" ALT="Figure 1"> View larger version (99K): org.highwire.dtl.DTLVardef@59d2dborg.highwire.dtl.DTLVardef@12244c4org.highwire.dtl.DTLVardef@d0a8a5org.highwire.dtl.DTLVardef@f01a4b_HPS_FORMAT_FIGEXP M_FIG C_FIG