APPLICATION OF THE MULTIMOLECULE AND MULTICONFORMATIONAL RESP METHODOLOGY TO BIOPOLYMERS - CHARGE DERIVATION FOR DNA, RNA, AND PROTEINS

We present the derivation of charges of ribo- and deoxynucleosides, nu cleotides, and peptide fragments using electrostatic potentials obtain ed from ab initio calculations with the 6-31G basis set. For the nucl eic acid fragments, we used electrostatic potentials of the four deoxy ribonucleosides (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nu cleotides are derived using multiple-molecule fitting and restrained e lectrostatic potential (RESP) fits,(1,2) with Lagrangian multipliers e nsuring a net charge of 0 or +/-1. We suggest that the preferred appro ach for deriving charges for nucleosides and nucleotides involves allo wing only C1' and H1' of the sugar to vary as the nucleic acid base, w ith the remainder of sugar and backbone atoms forced to be equivalent. For peptide fragments, we have combined multiple conformation fitting , previously employed by Williams(3) and Reynolds et al.,(4) with the RESP approach(1,2) to derive charges for blocked dipeptides appropriat e for each of the 20 naturally occuring amino acids. Based on our resu lts for propyl amine,(1,2) we suggest that two conformations for each peptide suffice to give charges that represent well the conformational ly dependent electrostatic properties of molecules, provided that thes e two conformations contain different values of the dihedral angles th at terminate in heteroatoms or hydrogens attached to heteroatoms. In t hese blocked dipeptide models, it is useful to require equivalent N-H and C=O charges for all amino acids with a given net charge (except pr oline), and this is accomplished in a straightforward fashion with mul tiple-molecule fitting. Finally, the application of multiple Lagrangia n constraints allows for the derivation of monomeric residues, with th e appropriate net charge from a chemically blocked version of the resi due. The multiple Lagrange constraints also enable charges from two or more molecules to be spliced together in a well-defined fashion. Thus , the combined use of multiple molecules, multiple conformations, mult iple Lagrangian constraints, and RESP fitting is shown to be a powerfu l approach to deriving electrostatic charges for biopolymers. (C) 1995 by John Wiley & Sons, Inc.