We desire to continue our studies of the nature and role of solvent in biological systems. A natural sequence of the work carried under the current period of the grant is the study of small molecule-protein interactions. We are thus planning to generalize and extend these studies to all the factors responsible for biological recognition at the molecular level as represented by this type of interaction. Small molecule-protein recognition is at the centre of much drug action, hormone response, nerve synapse function and enzyme catalysis and regulation. We propose to undertake a theoretical study of a structurally and thermodynamically well characterized case, the binding of inhibitors to lysozyme, with the aim of achieving understanding at the molecular level which in particular will be of direct application to the design of enzyme inhibitors which act as drugs. The methods of solvent simulation and analysis established during the current grant period will be used to study solvent changes on complex formation between the enzyme and an inhibitor. The questions addressed here will be: how does solvent behavior contribute to the enthalpy and entropy of binding? What aspects of the solute created environment are responsible for this behavior? What is the screening effect of the solvent structure on protein-ligand interactions? This last point together with an investigation of the induction effects in the protein and ligand will answer the long standing question, what is effective dielectric for such interactions? The picture of binding will be completed by calculation of the energy of pairwise atom-atom interactions between ligand and protein, with particular attention paid to their effective range; investigation of the energy associated with conformational change on complex formation; and comparison of the free energy of the normal modes of vibration of the protein in the present and absence of ligand. This last step is intended to clarify the role of low frequency 'breathing' modes in the expermentally observed entropy change.
| Kitson, D H; Avbelj, F; Moult, J et al. (1993) On achieving better than 1-A accuracy in a simulation of a large protein: Streptomyces griseus protease A. Proc Natl Acad Sci U S A 90:8920-4 |
| Avbelj, F; Moult, J; Kitson, D H et al. (1990) Molecular dynamics study of the structure and dynamics of a protein molecule in a crystalline ionic environment, Streptomyces griseus protease A. Biochemistry 29:8658-76 |
| Kitson, D H; Hagler, A T (1988) Theoretical studies of the structure and molecular dynamics of a peptide crystal. Biochemistry 27:5246-57 |
| Kitson, D H; Avbelj, F; Eggleston, D S et al. (1986) The structure, energy, entropy, and dynamics of peptide crystals. Ann N Y Acad Sci 482:145-62 |
| Moult, J; Sussman, F; James, M N (1985) Electron density calculations as an extension of protein structure refinement. Streptomyces griseus protease A at 1.5 A resolution. J Mol Biol 182:555-66 |
