Abstract
Maintaining a proper balance between specific intermolecular interactions and non-specific solvent interactions is of critical importance in molecular simulations, especially when predicting binding affinities or reaction rates in the condensed phase. The most rigorous metric for characterizing solvent affinity are solvation free energies, which correspond to a transfer from the gas phase into solution. Due to the drastic change of the electrostatic environment during this process, it is also a stringent test of polarization response in the model. Here, we employ both the CHARMM fixed charge and polarizable force fields to predict hydration free energies of twelve simple solutes. The resulting classical ensembles are then reweighted to obtain QM/MM hydration free energies using a variety of QM methods, including MP2, Hartree–Fock, density functional methods (BLYP, B3LYP, M06-2X) and semi-empirical methods (OM2 and AM1 ). Our simulations test the compatibility of quantum-mechanical methods with molecular-mechanical water models and solute Lennard–Jones parameters. In all cases, the resulting QM/MM hydration free energies were inferior to purely classical results, with the QM/MM Drude force field predictions being only marginally better than the QM/MM fixed charge results. In addition, the QM/MM results for different quantum methods are highly divergent, with almost inverted trends for polarizable and fixed charge water models. While this does not necessarily imply deficiencies in the QM models themselves, it underscores the need to develop consistent and balanced QM/MM interactions. Both the QM and the MM component of a QM/MM simulation have to match, in order to avoid artifacts due to biased solute–solvent interactions. Finally, we discuss strategies to improve the convergence and efficiency of multi-scale free energy simulations by automatically adapting the molecular-mechanics force field to the target quantum method.
Highlights
Biological systems are mostly composed of water, and the interactions with water are a central feature of life as we know it [1,2,3,4,5]
We computed hydration free energies for twelve simple solutes to determine an effective choice of quantum mechanical (QM) method to use in combination with explicit solvent
For QM/molecular mechanics (MM) hydration free energy calculations based on the CHARMM CHARMM General Force Field (CGenFF) fixed charge force field, the best results were obtained with the OM2 semi-empirical method (RMSD = 1.3 kcal/mol) and the BLYP method (RMSD = 1.4 kcal/mol)
Summary
Biological systems are mostly composed of water, and the interactions with water are a central feature of life as we know it [1,2,3,4,5]. Solvation influences a wide variety of processes, including protein folding [6,7,8,9,10], crystal polymorphism [11], conformational equilibria [12,13,14,15] and even basic reaction pathways [16]. Water is one of the main actors in the selectivity of biochemical interactions and has a profound influence on both the kinetics and thermodynamics of protein-protein, protein-nucleic acid and protein-ligand binding [17]. Any binding event between a ligand and a receptor in aqueous solution is first preceded by the desolvation of water molecules from the binding site and the ligand’s surface. Given the fundamental importance of the solvent, no biomolecular model is adequate without properly accounting for solvation
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