SEEKR: Simulation Enabled Estimation of Kinetic Rates, A Computational Tool to Estimate Molecular Kinetics and Its Application to Trypsin–Benzamidine Binding

Abstract

We present the Simulation Enabled Estimation of Kinetic Rates (SEEKR) package, a suite of open-source scripts and tools designed to enable researchers to perform multiscale computation of the kinetics of molecular binding, unbinding, and transport using a combination of molecular dynamics, Brownian dynamics, and milestoning theory. To demonstrate its utility, we compute the k_on, k_off, and ΔG_bind for the protein trypsin with its noncovalent binder, benzamidine, and examine the kinetics and other results generated in the context of the new software, and compare our findings to previous studies performed on the same system. We compute a k_on estimate of (2.1 ± 0.3) × 10⁷ M^-1 s^-1, a k_off estimate of 83 ± 14 s^-1, and a ΔG_bind of -7.4 ± 0.1 kcal·mol^-1, all of which compare closely to the experimentally measured values of 2.9 × 10⁷ M^-1 s^-1, 600 ± 300 s^-1, and -6.71 ± 0.05 kcal·mol^-1, respectively.