The orientation of N-H...O=C and N-H...N hydrogen bonds in biological systems: how good is a point charge as a model for a hydrogen bonding atom?

In order to design new ligands for protein-binding sites of unknown structure, it would be useful to predict the likely sites of hydrogen bonding of an unknown protein fragment to a known molecule. The positions of maxima and minima in the electrostatic potential at appropriate distances from the van der Waals surface were calculated for various small molecules, nucleic acid bases, peptide units and amino acid side chains containing groups which can form the biologically important N-H...O=C and N-H...N hydrogen bonds. Their ability to predict the positions of H and O/N in hydrogen bonded complexes, as predicted by optimising the electrostatic interactions of pairs of such molecules constrained by the molecular shapes, was assessed. It is shown that extrema in the electrostatic potential around the isolated molecules give worthwhile predictions for the locations of hydrogen binding partners. For molecules bound by a single N-H...O=C hydrogen bond, the electrostatic maximum associated with the H is usually less than 1 A from an acceptor atom, while a C=O electrostatic minimum is generally less than 1.5 A from the hydrogen bond proton. However, a significant number of hydrogen bonds form to the opposite lone pair from the electrostatic minimum, in which case the separation is up to 3.3 A. This reflects the broad electrostatic potential well around a carbonyl oxygen between the lone pair directions. The model predicts when neighbouring atoms drastically change the hydrogen bonding characteristics of an N-H or C=O group. Although the geometries of hydrogen bonded complexes are influenced by the other van der Waals contacts between the molecules, particularly multiple hydrogen bonds, these influences are constant when considering hydrogen bonding to a specific uncharacterised binding site. Hence, the consideration of sterically accessible electrostatic extrema will be useful in the design of new ligands.