Improving sampling of binding free energy differences between covalently bound ligands in alternate binding pockets using MT-REXEE

TL;DR

This paper introduces MT-REXEE, an enhanced sampling method that improves the efficiency and accuracy of free energy calculations in complex molecular systems with high energy barriers, demonstrated on a protein-ligand system.

Contribution

The paper presents MT-REXEE, a novel adaptive sampling approach that significantly enhances sampling efficiency for covalently bound ligands in multiple pockets, enabling better free energy estimates.

Findings

Faster convergence of free energy estimates with MT-REXEE.

Efficient sampling of multiple binding pockets in complex systems.

Open-source implementation available for broader use.

Abstract

The primary limitation for the application of alchemical free energy methods to a wider variety of complex molecular systems is achieving reasonable sampling. Flexible binding complexes often have high free energy barriers, which require prohibitively long simulations to sample sufficiently to obtain reliable free energy estimates. An example of such a system is the complex formed between FabB, an elongating \beta-ketoacyl-acyl carrier protein (ACP) synthase (KS) from Escherichia coli and ACP, which carries acyl chains of varying lengths. Previous experimental evidence suggests that growing acyl chains can bind to at least two pockets. With the multiple topology replica exchange of expanded ensemble (MT-REXEE) enhanced sampling approach, we can obtain highly efficient sampling of both pockets by adaptively growing and shrinking the chains in the simulation ensemble, allowing each simulation to visit chain lengths where transitions between the pockets do occur. This enables unbiased sampling of alternate configurational states for large complex systems. Using the new swapping approach gives significantly enhanced sampling even for this simpler problem, as demonstrated by faster convergence of free energy estimates. This case study demonstrates the utility of MT-REXEE and its open-source implementation for systems that feature high free energy barriers for a subset of ligands of interest, demonstrating a valuable addition to the existing stable of enhanced sampling methods.