Reduced point charge models of proteins: assessment based on molecular dynamics simulations

Abstract

A reduced point charge distribution is used to model Ubiquitin and two complexes, Vps27 UIM-1 -Ubiquitin and BarnaseBarstar. It is designed from local extrema in charge density distributions obtained from the Poisson equation applied to smoothed molecular electrostatic potentials. A variant distribution is built by locating point charges on atoms. Various charge fitting conditions are selected, i.e. from either electrostatic Amber99 (Assisted Model Building with Energy Refinement) Coulomb potential or forces, considering reference grid points located within various distances from the protein atoms, with or without separate treatment of main and side chain charges. The program GROMACS (Groningen Machine for Chemical Simulations) is used to generate Amber99SB molecular dynamics (MD) trajectories of the solvated proteins modelled using the various reduced point charge models (RPCMs) so obtained. Point charges that are not located on atoms are considered as virtual sites. Some RPCMs lead to stable MD trajectories. They, however, involve a partial loss in the protein secondary structure and lead to a less-structured solute solvation shell. The model built by fitting charges on Coulomb forces calculated at grid points ranging between 1.4 and 2.0 times the van der Waals radius of the atoms, with a separate treatment of main chain and side chain charges, appears to best approximate all-atom MD trajectories.

Reduced Point Charge Models of Proteins: Effect of Protein–Water Interactions in Molecular Dynamics Simulations of Ubiquitin Systems

“…The initial configurations were retrieved from the Protein Data Bank, and histidine residues occurring in 1Q0W, 2MBB, and 2G3Q were set, according to the PDB file content, to His+, Hisδ, and His+ protonation states, respectively. Two point charge distributions were considered, i.e., either the original Amber99sb atom point charges, or the corresponding RPCM parametrized from electrostatic forces of amino acids in various conformations . In that last case, the point charges are located on selected atoms, except for residues His+, Phe, and Trp where some of the side chain charges must be treated as virtual sites.…”

“…All end residues bear an extra charge on either N (of NH 3 ) or O (of COO – ). A full description of the models can be found in the Supporting Information File SI4 of a previous paper . Coordinates and topology files of the initial MD conformations are provided in Supporting Information (Annex S1).…”

“…In the present paper, we investigate the influence of various solvent models on the protein–water interface of ubiquitin complexes modeled using different point charge distributions, and their consequences on the MD trajectory stability. In particular, a previously developed reduced point charge model (RPCM) for proteins is tested for solvated ubiquitin complexes and compared to its all-atom (AA) version. It was indeed previously shown that the nature of the solvent can strongly affect the dynamics and structure of ubiquitin described with a RPCM .…”

“…That aspect is important to be evaluated when, for example, one wishes to consider large protein systems with hybrid point charge distributions, involving a combination of AA and RPCM charges. Besides the already considered TIP4P-Ew water FF, a rigid four-site model used before, ,, we also apply the less time-consuming TIP3P FF, a rigid three-site model. Additionally, we have used two approaches to modulate the protein–water interactions, i.e., either a scaling of the Lennard-Jones (LJ) protein–O water interaction parameters according to the approach of Best et al, or the combination of the TIP3P water model with the coarse-grain (CG) SIRAH water description …”

Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase

“…The following references are cited in the supporting information for this article: Besler et al (1990), Borodin & Smith (2009), Frisch et al (2009), Leherte (2016), Machado (2018), Pedretti et al (2004) and Singh & Kollman (1984).…”