Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning

Abstract

The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the kon rate constant for superoxide dismutase with its natural substrate, O2 −, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the kon for a new system: the N-terminal domain of Troponin C with its natural substrate Ca2+. The kon calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor.

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

“…Additional scripts used to generate some of the figures and data are also included in the SEEKR package. Error estimates were computed according to our previously defined procedure 31 .…”

“…In our previous study, we presented a hybrid MD/BD/milestoning methodology to conduct our investigations into the kinetics of binding between superoxide dismutase and its natural substrate, the superoxide anion, and between troponin C and its natural substrate, the calcium ion. 31 Here, we make available a software package, SEEKR, that implements this method with significant improvements in automation, usability, and analysis. We demonstrate the utility of SEEKR by applying it to estimate the k on , the k off , and Δ G bind between the serine protease trypsin and its ligand, benzamidine.…”

Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time

“…The drug binding rate has traditionally been a quantity of interest in the field of drug discovery, fueling numerous in silico studies of binding kinetics. 7–9,16,18,20 However, dissociation rates are increasingly considered an equally important indicator of drug efficacy 13,14 and efforts are being made to develop computational means of determining these rates. 15–18 The complexity of unbinding processes underlies the difficulty of obtaining dissociation rates.…”

Molecular Simulations Reveal an Unresolved Conformation of the Type IA Protein Kinase A Regulatory Subunit and Suggest Its Role in the cAMP Regulatory Mechanism

“…The diffusion of cAMP, a polar molecule, is likely influenced by long-range electrostatic forces which are estimated computationally by Brownian Dynamics (BD) simulation methods. 22–24 …”