Skip to main content
Open Access Publications from the University of California

UC Irvine

UC Irvine Previously Published Works bannerUC Irvine

Kinetics and free energy of ligand dissociation using weighted ensemble milestoning.

Published Web Location Commons 'BY' version 4.0 license

We consider the recently developed weighted ensemble milestoning (WEM) scheme [D. Ray and I. Andricioaei, J. Chem. Phys. 152, 234114 (2020)] and test its capability of simulating ligand-receptor dissociation dynamics. We performed WEM simulations on the following host-guest systems: Na+/Cl- ion pair and 4-hydroxy-2-butanone ligand with FK506 binding protein. As a proof of principle, we show that the WEM formalism reproduces the Na+/Cl- ion pair dissociation timescale and the free energy profile obtained from long conventional MD simulation. To increase the accuracy of WEM calculations applied to kinetics and thermodynamics in protein-ligand binding, we introduced a modified WEM scheme called weighted ensemble milestoning with restraint release (WEM-RR), which can increase the number of starting points per milestone without adding additional computational cost. WEM-RR calculations obtained a ligand residence time and binding free energy in agreement with experimental and previous computational results. Moreover, using the milestoning framework, the binding time and rate constants, dissociation constants, and committor probabilities could also be calculated at a low computational cost. We also present an analytical approach for estimating the association rate constant (kon) when binding is primarily diffusion driven. We show that the WEM method can efficiently calculate multiple experimental observables describing ligand-receptor binding/unbinding and is a promising candidate for computer-aided inhibitor design.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View