MODELING AMINO-ACID SIDE-CHAINS .3. INFLUENCE OF INTRAMOLECULAR AND INTERMOLECULAR ENVIRONMENT ON POINT CHARGES

Modifications of the molecular charge distributions of simplified models of amino acids due to intra- and intermolecular environment have been analyzed. Point charges of the extended conformers of Me-L-Ala-Me, Me-L-Asp-Me, Me-Gly-Me, Me-L-Ser-Me, and the extended (C5) as well as the C-7-equatorial conformations of N-acetyl-N'-methyl-L-aspartylamide (NANMAsp) have been computed from ab initio optimized geometries, using the split-valence 6-31G** basis set. Point charge models were determined from the resulting self-consistent-field (SCF) wave functions by means of least-squares fits to the exact ab initio electrostatic potential and to the approximate electrostatic potential created by distributed multipole moments (DMM). The results show that the charge distribution of the side chain is affected by that of the backbone. In turn, the conformation of the backbone, and hence its charges, are altered, depending on the polarity of the side chain. In addition, the distortion of the total molecular charge distribution caused by conformational changes strongly suggests that conventional models are unable to provide point charges that are conformationally invariant. Moreover, the computed quasi-conformation-independent charges obtained from DMM potentials support the view that it is impossible to obtain conformationally invariant atomic point charge models of good quality. The effects of the solvent on point charge models have also been considered at two levels of approximation. First, a cavity model of solvation has been used to represent the bulk aqueous solution. 6-31G** ab initio polarized wave functions have been employed to study the influence of the continuum on the charge distribution of a series of model amino acid side chains, revealing that charges depend on the surroundings. Second, in the framework of a supermolecule model, and in order to understand the role of the first solvation shell, two hydrated complexes of the model aspartate side chain have been optimized in both vacuum and aqueous solution, using the 6-31G** basis set. Point charges were computed using the corresponding accurate wave functions. The significant charge transfer observed from these results indicates that it is necessary to employ a combined discrete-continuum model of solvation for the treatment of explicit hydration.