DEVELOPMENT OF MODIFIED FORCE-FIELD FOR CATION-AMINO ACID INTERACTIONS - AB INITIO-DERIVED EMPIRICAL CORRECTION TERMS WITH COMMENTS ON CATION-PI INTERACTIONS

The modeling of voltage-gated ion-channel proteins is a continuing cha llenge for force-field calculations because of the diverse range of in teractions involved. In particular, current force fields are not param eterized for either ion-amino acid or amino acid-electric field intera ctions. To address the parameterization of ion-amino acid interactions , we have tested the use of empirical correction terms, derived from a b 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, cys teine, methionine, lysine, arginine, aspartate, histidine (uncharged), tyrosine, tryptophan, and phenylalanine, both completes the parameter ization of the molecular environments contained in the amino acids, an d allows specific comment on these ion-functional group interactions. The cation-pi interactions were of particular interest, given recent p roposals in the literature and the fear that force fields would not be able to treat such interactions. We present a comprehensive compariso n of the ab initio (DFT [BLYP], 6-311 G*) and force field (CHARMm22.0 ) assessments of these interactions. (C) 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1515-1525, 1998.