Understanding drug-protein binding thermodynamics, together with their binding kinetic behavior, is critical for rational drug discovery. Binding kinetics can also be a critical differentiator and predictor of drug efficacy and safety. However, the free energy profile, including the free energy barriers that determine drug binding kinetics cannot be constructed easily. Here, we introduce an interactive toolkit, termed BKiT, to estimate drug unbinding free energy profile and allow researcher to visualize events with atomistic details at energy barriers. We sampled xk263-HIVp dissociation trajectory using accelerated molecular dynamics (aMD) with reseeding approach. We reduced the degree of freedom of ligand-protein system to only two by applying principal component (PC) analysis on selected atoms. Milestones (MS) were assigned along the dissociation pathway on PC space. Frames within 1 Angstrom of milestones were selected and screened to ensure smooth ligand transition between milestones. Short classical MDs were sampled using frames on MS as initial conformations to calculate ligand transition time and rate between milestones. Binding free energy and local energy barriers were calculated with transition kernel matrix. BKiT is user-friendly and efficient toolkit to investigate ligand binding free energy.

Binding kinetic toolkit (BKiT): Interactive toolkit for binding free energy estimation of ligand-protein systems using milestoning theory

ACS Spring 2022

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