Why protein conformers in molecular dynamics simulations differ from their crystal structures: a thermodynamic insight

Conformers generally deviate structurally from their starting X-ray crystal structures early in moleculardynamics (MD) simulations. Studies have recognized such structural differences and attempted to provide an explanationfor and justify the necessity of MD equilibrations. However, a detailed explanation based on fundamental physics andvalidation on a large ensemble of protein structures is still missing. Here we provide the first thermodynamic insightsinto the radically different thermodynamic conditions of crystallization solutions and conventional MD simulations.Crystallization solution conditions can lead to nonphysiologically high ion concentrations, low temperatures, and crystalpacking with strong specific protein–protein interactions, not present under physiological conditions. These differencesaffect protein conformations and functions, and MD structures equilibrated or simulated under physiological conditionsare usually expected to differ from their X-ray structures at a local scale, while the global fold is usually maintained.To quantify this property, we performed conventional MD simulations for over 70 different proteins spanning a broadrange of molecular size and structural and functional families. Our analysis shows that crystal structures are goodstarting points; however, they do not represent structures in their physiological environment. This fact has to be takeninto consideration when computational methods dependent on atomic coordinates, such as substrate/ligand docking, areused to guide experimental analyses.

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