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

Modifications of the molecular charge distributions of simplified mode ls of amino acids due to intra- and intermolecular environment have be en 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, usi ng the split-valence 6-31G* basis set. Point charge models were deter mined from the resulting self-consistent-field (SCF) wave functions by means of least-squares fits to the exact ab initio electrostatic pote ntial and to the approximate electrostatic potential created by distri buted multipole moments (DMM). The results show that the charge distri bution 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 distort ion of the total molecular charge distribution caused by conformationa l changes strongly suggests that conventional models are unable to pro vide point charges that are conformationally invariant. Moreover, the computed quasi-conformation-independent charges obtained from DMM pote ntials support the view that it is impossible to obtain conformational ly invariant atomic point charge models of good quality. The effects o f the solvent on point charge models have also been considered at two levels of approximation. First, a cavity model of solvation has been u sed to represent the bulk aqueous solution. 6-31G* ab initio polarize d wave functions have been employed to study the influence of the cont inuum 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 mode l aspartate side chain have been optimized in both vacuum and aqueous solution, using the 6-31G* basis set. Point charges were computed usi ng the corresponding accurate wave functions. The significant charge t ransfer observed from these results indicates that it is necessary to employ a combined discrete-continuum model of solvation for the treatm ent of explicit hydration.