Development of modified force field for cation-amino acid interactions:Ab initio-derived empirical correction terms with comments on cation-? interactions

The modeling of voltage-gated ion-channel proteins is a continuing challenge for force-field calculations because of the diverse range of interactions involved. In particular, current force fields are not parameterized for either ion–amino acid or amino acid–electric field interactions. To address the parameterization of ion–amino acid interactions, we have tested the use of empirical correction terms, derived from ab initio calculations of single amino acids (representing the peptide backbone) interacting with K+ ions. Having demonstrated the utility of such an approach, we then extended the application to the amino acid side chains. The calculation of the interaction of K+ with serine, cysteine, methionine, lysine, arginine, aspartate, histidine (uncharged), tyrosine, tryptophan, and phenylalanine, both completes the parameterization of the molecular environments contained in the amino acids, and allows specific comment on these ion–functional group interactions. The cation–π interactions were of particular interest, given recent proposals in the literature and the fear that force fields would not be able to treat such interactions. We present a comprehensive comparison of the ab initio (DFT [BLYP], 6-311 G**) and force field (CHARMm22.0) assessments of these interactions.