Evaluation of reduced point charge models of proteins through Molecular Dynamics simulations: Application to the Vps27 UIM-1–Ubiquitin complex

• Reduced point charge models provide stable Molecular Dynamics trajectories of the protein complex.
• H-bond networks are progressively modified as the reduction degree increases.
• The models allow to probe local potential hyper-surface minima that are similar to all-atom ones.
• The models allow to sample protein conformations more rapidly than the all-atom case due to a lowering of energy barriers.
• Implementation of point charges as virtual sites requires attention to the reference atoms and to the Cb-14 energy terms.

Reduced point charge models of amino acids are designed, (i) from local extrema positions in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions, and (ii) from local maxima positions in promolecular electron density distribution functions. Corresponding charge values are fitted versus all-atom Amber99 MEPs. To easily generate reduced point charge models for protein structures, libraries of amino acid templates are built. The program GROMACS is used to generate stable Molecular Dynamics trajectories of an Ubiquitin-ligand complex (PDB: 1Q0W), under various implementation schemes, solvation, and temperature conditions. Point charges that are not located on atoms are considered as virtual sites with a nul mass and radius. The results illustrate how the intra- and inter-molecular H-bond interactions are affected by the degree of reduction of the point charge models and give directions for their implementation; a special attention to the atoms selected to locate the virtual sites and to the Coulomb-14 interactions is needed. Results obtained at various temperatures suggest that the use of reduced point charge models allows to probe local potential hyper-surface minima that are similar to the all-atom ones, but are characterized by lower energy barriers. It enables to generate various conformations of the protein complex more rapidly than the all-atom point charge representation.

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