Transferability of conformational dependent charges from protein simulations

We have studied the transferability of atomic charges for proteins, fitted to the quantum mechanical electrostatic potential and extensively averaged over a set of structures sampled by molecular dynamics (MD) and over all residue of the same kind in the protein sequence (xAvESP). Previously, such charges were obtained for one single protein (avidin). In this study, we employ five additional proteins. The aim of this study is fourfold. First, we provide xAvESP charges for all amino acids, including aminoand carboxy-terminal variants of all, as well as alternative protonation states of His, Asp, Glu, Lys, Arg, Cys, and Tyr. Second, we show that the xAvESP charges averaged over the five new proteins are similar to charges obtained in the same way for avidin, with a correlation coefficient of 0.997. This shows that the charges are transferable and system-independent. Electrostatic protein–ligand interaction energies calculated with charges obtained from different proteins differ by only 1–3 kJ/mol on average. The xAvESP charges correlate rather well with Amber charges (except for the N atom of amino-terminal residues), although they are obtained in a more general way. Third, the conformational dependence of the charges is significant and gives rise to quite large differences in energies. However, these differences are to a large extent screened by solvation effects. For example, the solvent-screened electrostatic interaction energy between the protein galectin-3 and five different ligands varies with the charge sets by less than 3 kJ/mol on average. Finally, we show that the xAvESP charges give a comparable root-mean-squared deviation as the Amber charges for the MD simulations of 18 protein–ligand complexes, they give comparable or slightly worse backbone N–H order parameters for two galectin-3 complexes, but they give a better correlation between calculated and experimental affinities for the binding of seven biotin analogues to avidin and for nine inhibitors of factor Xa.