Improved intermolecular force field for molecules containing H, C, N, and O atoms, with application to nucleoside and peptide crystals

A new intermolecular force field for nitrogen atoms in organic molecules wa s derived from a training dataset of 76 observed azahydrocarbon crystal str uctures and 11 observed heats of sublimation. The previously published W99 force field for hydrogen, carbon, and oxygen was thus extended to include n itrogen atoms. Nitrogen atoms were divided into four classes: N(1) for trip ly bonded nitrogen, N(2) for nitrogen with no bonded hydrogen (except the t riple bonded case), N(3) for nitrogen with one bonded hydrogen, and N(4) fo r nitrogen with two or more bonded hydrogens. H(4) designated hydrogen bond ed to nitrogen. Wavefunctions of 6-31g** quality were calculated for each m olecule and the molecular electric potential (MEP) was modeled with net ato mic and supplementary site charges. Lone pair electron charge sites were in cluded for nitrogen atoms where appropriate, and methylene bisector charges were used for CH2 and CH3 groups when fitting the MEP. X-H bond distances were set to standard values for the wave function calculation and then fore shortened by 0.1 Angstrom for the MEP and force field fitting. Using the fo rce field optimized to the training dataset, each azahydrocarbon crystal st ructure was relaxed by intermolecular energy minimization. Predicted maximu m changes in unit cell edge lengths for each crystal were 3% or less. The c omplete force field for H, C, N, and O atoms was tested by intermolecular e nergy relaxation of nucleoside and peptide molecular crystals. Even though these molecules were not included in any of the training datasets for the f orce field, agreement with their observed crystal structures was very good, with predicted unit cell edge shifts usually less than 2%. These tests inc luded crystal structures of representatives of all eight common nucleosides found in DNA and RNA, 15 dipeptides, four tripeptides, two tetrapeptides, and a pentapeptide with two molecules in the asymmetric unit. (C) 2001 John Wiley & Sons, Inc.