University of Oxford,Laboratory of Molecular Biophysics,
The Rex Richards Building,South Parks Road, Oxford OX1 3QU.
Hydrogen-bonds play a crucial role in determining the specificity of ligand binding. Their important contribution is explicitly incorporated into a computational method, called GRID, which has been designed to detect energetically favourable ligand binding sites on a chosen target molecule of known structure. An empirical energy function consisting of a Lennard-Jones, an electrostatic and a hydrogen-bonding term is employed. The latter term is found to be necessary because spherically symmetric atom centred forces alone may not adequately reproduce the geometry of two interacting molecules. The hydrogen-bonding term is dependent on the length and orientation of the hydrogen-bond. Its functional form also varies according to the chemical nature of both the hydrogen-bond donor and acceptor atoms, and has been modelled to fit experimental observations of crystal structures. The mobility of the hydrogen-bonding hydrogens is considered analytically in calculating the hydrogen-bond energy. The hydrogen-bonding energy functions will be described and their application will be demonstrated on molecules of pharmacological interest where hydrogen-bonds influence the binding of ligands.
In ``Computer-assisted Modeling of Receptor-Ligand Interactions. Theoretical Aspects and Applications to Drug Design''
Ed. Golombek,A., Alan R. Liss, Inc. New York
Prog. Clin. Biol. Res. (1989) 289 pp433-444