More details about our research interests

The good news is that the computer programs correctly identify substrate binding sites for enzymes where these have been determined by crystallographic measurements. Also, in the case of at least one enzyme, hexokinase from yeast, they correctly predict the site on the substrate upon which a modification can yield an active alternative substrate. Thus, part of our research effort involves applying these new methods of structure-based drug design to macromolecular systems of pharmaceutical interest and measuring the corresponding experimental biochemical equilibria. We also are undertaking the determination of new protein structures of pharmaceutical interest.

The bad news is that the programs, as most others, are based on empirically determined potential energy functions which have been extrapolated from simple compounds, ignoring certain classes of known intermolecular interactions. Although such empirical energy potentials predict large binding affinity differences rapidly and relatively reliably, predictions of small differences in binding energy are less reliable and require more extensive calculations. One reason for the neglect of certain intermolecular interactions in many calculations is that we lack an extensive experimental database of measurements of such interactions. To alleviate this situation, part of our research effort is directed toward developing techniques for the measurement and analysis of intemmolecular interactions between biological molecules.

Two approaches toward the measurement of the effects of polarization upon intermolecular interactions are being pursued. The first of these involves the measurement of the structural changes and packing rearrangements of molecules within crystals of biological molecules upon application of external electric fields of known strengths to these crystals. The second of these approaches involves the synthesis of model organic compounds for which chelation of metal cations at a defined site affects the strength of intermolecular interactions involving a distant part of the molecule.

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