Scalable Constant pH Molecular Dynamics in GROMACS

18 January 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Molecular dynamics (MD) computer simulations are used routinely to compute atomistic trajectories of complex systems. Systems are simulated in various ensembles, depending on the experimental conditions one aims to mimic. While constant energy, temperature, volume, and pressure are rather straightforward to model, pH, which is an equally important parameter in experiments, is more difficult to account for in simulations. Although a constant pH algorithm based on the $\lambda$-dynamics approach by Brooks and co-workers was implemented in a fork of the GROMACS molecular dynamics program, uptake has been rather limited, presumably due to the poor scaling of that code with respect to the number of titratable sites. To overcome this limitation, we implemented an alternative scheme for interpolating the Hamiltonians of the protonation states that makes the constant pH molecular dynamics simulations almost as fast as a normal MD simulation with GROMACS. In addition, we implemented a simpler scheme, called multisite representation, for modeling side chains with multiple titratable sites, such as imidazole rings. This scheme, which is based on constraining the sum of the $\lambda$-coordinates, not only reduces the complexity associated with parameterizing the intra-molecular interactions between the sites, but is also easily extendable to other molecules with multiple titratable sites. With the combination of a more efficient interpolation scheme and multisite representation of titratable groups, we anticipate a rapid uptake of constant pH molecular dynamics simulations within the GROMACS user community.

Keywords

GROMACS
Molecular dynamics
Constant pH simulations
Lambda dynamics

Supplementary materials

Title
Description
Actions
Title
Fitting code
Description
Mathematica notebook with the implemented algorithm for fitting polynomials to gradients obtained from TI runs of reference state
Actions
Title
Zip file with all the parameters used in the simulation
Description
In this file, all the information needed to reproduce our simulations is provided: force field parameters, input files, etc.
Actions
Title
Scalable constant pH in GROMACS SI
Description
The Supporting information file, where the description of lambda-potentials, effect of neglecting the interpolation of Lennard-Jones interactions, titration results for Asp and Glu within the single-site representation, a comparison of pKa values for HEWL obtained with various lambda-dynamics-based constant pH methods, demonstration that charge interpolation requires a single evaluation of the electrostatic potential for both single- and multisite representations, and introduction into routines to fit V^MM.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.