Multidimensional Replica Exchange simulations for Efficient constant pH and Redox Potential Molecular Dynamics

TL;DR

This paper introduces multidimensional replica exchange molecular dynamics simulations incorporating pH and redox potential, demonstrating improved sampling efficiency and convergence with manageable computational costs, validated on a small heme-containing system.

Contribution

It is the first to implement and analyze multidimensional REMD with pH and redox potential in AMBER, extending beyond temperature and Hamiltonian dimensions.

Findings

2D-REMD improves sampling over 1D-REMD

3D-REMD further enhances convergence

Computational cost remains manageable despite increased replicas

Abstract

Efficient computational methods that are capable of supporting experimental measures obtained at constant values of pH and redox potential are important tools as they serve to, among other things, provide additional atomic level information that cannot be obtained experimentally. Replica Exchange is an enhanced sampling technique that allows converged results to be obtained faster in comparison to regular molecular dynamics simulations. In this work we report the implementation, also available with GPU-accelerated code, of pH and redox potential (E) as options for multidimensional REMD simulations in AMBER. Previous publications have only reported multidimensional REMD simulations with the temperature and Hamiltonian dimensions. In this work results are shown for N-acetylmicroperoxidase-8 (NAcMP8) axially connected to a histidine peptide. This is a small system that contains only a single heme group. We compare results from E,pH-REMD, E,T-REMD and E,T,pH-REMD to one dimensional REMD simulations and to simulations without REMD. We show that 2D-REMD simulations improve sampling convergence in comparison to 1D-REMD simulations, and that 3D-REMD further improves convergence in comparison to 2D-REMD simulations. Also, our computational benchmarks show that our multidimensional REMD calculations have a small and bearable computational performance, essentially the same as one dimensional REMD. However, in multidimensional REMD a significantly higher number of replicas is required as the number of replicas scales geometrically with the number of dimensions, which requires additional computational resources. In addition to the pH dependence on standard redox potential values and the redox potential dependence on pKa values,we also investigate the influence of the temperature in our results. We observe an agreement between our computational results and theoretical predictions.