HYDRATION OF CIS AND TRANS N-METHYLFORMAMIDE AS REVEALED BY THE USE OF O-17-NMR, MOLECULAR MECHANICS, AND AB-INITIO CALCULATIONS

The solvation of cis and trans N-methylformamide (NMF) by water was in vestigated using a combination of O-17-nmr spectroscopy, classical mol ecular mechanics [MM2(77) and Mm2(87)] force field, and ab initio 4-31 G gradient optimization calculations. In dilute aqueous solution, the O-17-nmr spectra of NMF indicate strong shielding by 66.9 and 66.1 pp m for the cis and trans amide oxygens, respectively, compared to those values obtained in dilute toluene solution. This demonstrates that bo th isomers are equally solvated by molecules of water, which are furth er hydrogen bonded to molecules of water of the bulk solvent. Molecula r mechanics simulations were carried out for cis and trans NMF in a cl uster of water molecules. Radial distribution functions show structura l contacts by several water molecules at the amide CO and NH group, wh ich are significantly more pronounced with MM2(87) calculations. Ab in itio 4-31G gradient optimization calculations on the supermolecule tr ans NMF-(H2O)(3) indicates the presence of more than two hydrogen-bond contacts at the carbonyl oxygen. This is in agreement with MM2 calcul ations and provides further evidence for multiple acceptor properties of the amide oxygen and an out of the amide plane arrangement of the b ound molecules of water. Comparison of the integration data to the fir st radial distribution function (rdf) minima shows that the local solv ation of CO and NH groups is very similar for both cis and trans isome rs. The intermolecular geometric parameters of the supermolecule trans NMA-(H2O)(3) and the first rdf maxima resulting from Mm2(87) and MM2( 77) calculations are compared with distribution of water molecules aro und the CO and NH groups of peptides and proteins resulting from x-ray and neutron diffraction experiments. The rdfs involving the methyl gr oup of NMF demonstrate the nonrandom distribution of solvent sites wit h first maxima in reasonable agreement with distribution water molecul es around the apolar side chain of amino acid residues in proteins. (C ) 1995 John Wiley & Sons, Inc.