Toward a coarse-grained protein model coupled with a coarse-grained solvent model: Solvation free energies of amino acid side chains

Recently, we reported that molecular dynamics (MD) simulations using a coarse-grained (CG) peptide model coupled with a CG water model are able to reproduce many of the structural and thermodynamic features of short peptides with nonpolar side chains at 10³ times the normal speed (JCTC, 2007, 3, 2146−2161). To further develop a CG protein model for MD simulations, we systematically parametrized the side chains of all 20 naturally occurring amino acids. We developed the parameters by fitting the dihedral potentials of 13 small molecules, the densities and self-solvation free energies of liquids of eight organic molecules, and the hydration free energies of 35 small organic molecules. In a set of 11 classes of compounds (105 in total) including alkanes, alcohols, ethers, ketones/aldehydes, amines, amides, aromatics, carboxylic acids, sulfides/thiols, alkyl ammoniums, and carboxylate ions, the average error in the calculated hydration free energies compared with experimental results is about 1.4 kJ/mol. The average error in the calculated transfer free energies of the 19 side-chain analogues of amino acids from cyclohexane to water is about 2.2 kJ/mol. These results are comparable to the results of all-atom models.