Abstract:We present the derivation of a new molecular mechanical force field for simulating the structures, conformational energies, and interaction energies of proteins, nucleic acids, and many related organic molecules in condensed phases. This effective two-body force field is the successor to the Weiner et al. force field and was developed with some of the same philosophies, such as the use of a simple diagonal potential function and electrostatic potential fit atom centered charges. The need for a 10-12 function for representing hydrogen bonds is no longer necessary due to the improved performance of the new charge model and new van der Waals parameters. These new charges are determined using a 6-31G* basis set and restrained electrostatic potential (RESP) fitting and have been shown to reproduce interaction energies, free energies of solvation, and conformational energies of simple small molecules to a good degree of accuracy. Furthermore, the new RESP charges exhibit less variability as a function of the molecular conformation used in the charge determination. The new van der Waals parameters have been derived from liquid simulations and include hydrogen parameters which take into account the effects of any geminal electronegative atoms. The bonded parameters developed by Weiner et al. were modified as necessary to reproduce experimental vibrational frequencies and structures. Most of the simple dihedral parameters have been retained from Weiner et al., but a complex set of 4 and yj parameters which do a good job of reproducing the energies of the low-energy conformations of glycyl and alanyl dipeptides has been developed for the peptide backbone.

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We present the derivation of charges of ribo-and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calculations with the 6-31G" basis set. For the nucleic acid fragments, we used electrostatic potentials of the four deoxyribonucleosides (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-molecule fitting and restrained electrostatic potential (RESP) fits,', with Lagrangian multipliers ensuring a net charge of 0 or fl. We suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1' and H1' of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equivalent. For peptide fragments, we have combined multiple conformation fitting, previously employed by Williams3 and Reynolds et a1. : with the RESP approach',' to derive charges for blocked dipeptides appropriate for each of the 20 naturally occuring amino acids. Based on our results for propyl arnine,'T2 we suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of molecules, provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms. In these 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 proline), and this is accomplished in a straightforward fashion with multiple-molecule fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chemically blocked version of the residue. 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, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers. 0 1995