Apaya, Robert Patrick; (1997) The electrostatic interactions of protein-binding ligands. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A method for determining the relative binding orientation of different ligands within an unknown binding site is developed. By overlaying the maxima and minima in the electrostatic potential outside ligands, it is possible to match regions where strong electrostatic interactions, including hydrogen bonds, with binding site residues may be possible. This method of matching the potential extrema is in line with the belief that electrostatic complementarity plays a vital role in some molecular recognition processes. A key feature of this approach is the accurate calculation of the electrostatic potential, derived from a distributed multipole analysis (DMA) of an ab initio charge density of the molecule, which correctly represents the effects of anisotropy in the molecular charge density, eliminating the uncertainties arising from other approximate methods of representing molecular charge distributions. The method has been applied to the phosphodiesterase (PDE) III substrate adenosine- 3'5'-cyclic monophosphate (cAMP) and a range of inhibitors. Despite the structural variation between cAMP and the inhibitors, a plausible relative binding orientation can be found for each inhibitor, in which they are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This method has also been applied to other systems, including the substrate and inhibitors for the enzyme Glycolate Oxidase, for which information about the binding site structure is available. The method has generally predicted binding orientations obtained by optimizing the electrostatic interactions of each inhibitor within the binding site. The use of electrostatic extrema in predicting the positions of H and O in hydrogen bonded complexes has been examined for various small molecules modelling biologically important N-H–O=C hydrogen bonding interactions. Optimising the electrostatic interactions of pairs of these molecules in hydrogen bonded geometries has shown that the electrostatic extrema correlate with the positions of hydrogen bond donor and acceptor atoms. Thus, the theoretical basis of the approach is justified, and the method has been validated for use when the binding site structure is unavailable.

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