Constant pH molecular dynamics simulations: Current status and recent applications

ElsevierVolume 77, December 2022, 102498Current Opinion in Structural BiologyAbstract

Many important protein functions are carried out through proton-coupled conformational dynamics. Thus, the ability to accurately model protonation states dynamically has wide-ranging implications. Over the past two decades, two main types of constant pH methods (discrete and continuous) have been developed to enable proton-coupled molecular dynamics (MD) simulations. In this short review, we discuss the current status of the development and highlight recent applications that have advanced our understanding of protein structure-function relationships. We conclude the review by outlining the remaining challenges in the method development and projecting important areas for future applications.

Introduction

Many important biological functions are mediated by the so-called proton-coupled conformational dynamics, whereby titration of often one or two amino acid sidechains accompany a large conformational change in the protein. Such processes cannot be directly modeled by conventional molecular dynamics (cMD) simulations, as the protonation states are preassigned and fixed. Instead, it is desirable to perform MD at constant pH such that protonation states are allowed to switch in response to the change of conformational environment at a specified solution pH, i.e., simultaneous sampling of conformation and protonation states. Another use of constant pH MD is to determine the protonation and tautomer states of protein sidechains, which are largely invisible to experimental techniques [1].

Section snippetsCurrent status of constant pH molecular dynamics methods

Since the report of arguably the first constant pH MD simulation by Baptista et al., in 1997 [2], two main types of constant pH methods have been developed. The discrete constant pH framework [2, 3, 4, 5, 6, 7, 8, 9], makes use of a hybrid MD/Monte Carlo (MC) approach, in which an MD trajectory is periodically interrupted by attempts to switch a protonation state based on the Metropolis criterion (Figure 1a). A straightforward implementation of this approach is to perform MC sampling on

Comparison of constant pH methods

There are advantages and drawbacks to both constant pH frameworks. The major advantages of the discrete framework are physical representation of protonation states, straightforward implementation, and incorporation of nonbonded terms and tautomer states. A drawback is slower convergence [8,25], since typically one protonation state can be switched in each MC cycle. An additional limitation of the all-atom neMD/MC approach is the need for the “inherent” (guess) pKa's which should be close to the

Protonation states of enzyme active sites

A major application of constant pH MD is to predict the protonation states of enzyme active-site residues which often have highly shifted pKa's relative to model values in solution. While PB and empirical calculations are faster, the calculated pKa's are sensitive to input structures and parameters (e.g., protein dielectric constant in PB calculations) [32]. Using the hybrid-solvent MD/MC method [8], Hofer et al. [33] calculated the macroscopic pKa's of the active-site aspartates and histidines

Protonation state change of ligand

The aforementioned hybrid-solvent MD/MC simulations [8] of GART [36] showed that binding-induced protonation state change of the ligand which in turn perturbed the local hydrogen bonding.

pH-dependent protein-ligand and protein-protein binding

According to the Wyman linkage relation [50], the slope of the pH-dependent binding-free energy change is proportional to the difference in the net charge (or number of bound protons) between the bound and unbound states. Analytic integration of this relation [51, 52, 53] allows the calculation of the

pH- or protonation-dependent enzyme activities

Enzyme function often involves a protonation-state-dependent conformational change of an important loop, for example, the “flap” in aspartyl proteases. The hybrid-solvent CpHMD [23] simulations revealed that pepstatin binding introduces a pH-dependent dynamics for the flap in plasmepsin II [56].

The aforementioned hybrid-solvent MD/MC simulations of GART [36]. suggested that the pH-dependent activity change is due to the order-disorder transition of the activation loop which is promoted by the

Challenges and outlook

The application studies discussed in this review demonstrated the utilities and enormous potential of constant pH MD to provide novel insights and advance the understanding of important biological phenomena that are difficult to elucidate with wet-lab experiments alone. Despite the progress, further development of constant pH methods is needed. While the implicit- and hybrid-solvent constant pH methods are useful for certain applications, all-atom constant pH methods are in principle most

Papers of particular interest published within the period of review•

By combining CpHMD and umbrella sampling, the paper illuminated the proton-coupled lipid permeation process of a drug [60].

This work showed that by allowing proton titration, the DFG and αC-helix motion of kinases can be directly sampled [58].

This paper made a convincing case for the need of including pH effect in calculating protein-ligand binding-free energies [54].

A thorough study that contains novel analyses, e.g., catalytically competent protonation states and thermodynamic network [36].

An

Declaration of competing interest

J.S. is a founder and scientific advisor of ComputChem LLC and a scientific advisory board member of MatchPoint Therapeutics.

Acknowledgements

We acknowledge the National Institutes of Health (grants R01GM098818 and R01CA256557) for financial support.

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