Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics

J Phys Chem Lett. 2024 Oct 24;15(42):10473-10478. doi: 10.1021/acs.jpclett.4c02332. Epub 2024 Oct 11.

Abstract

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.

MeSH terms

  • Kinetics
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein-Tyrosine Kinases* / chemistry
  • Protein-Tyrosine Kinases* / metabolism
  • Thermodynamics

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases