THEORETICAL STUDIES OF PROTEIN LIGAND INTERACTIONS

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Thermodynamic simulation methods can now provide detailed atomic level information on structure-thermodynamic relationships for proteins and biopolymers in solution. The continued development and application of these new methods will be addressed in the proposed studies. These techniques, together with methods to compute free energies, energies and entropies will be applied to study three fundamental areas of biophysics: (i) conformational influences in enzyme-inhibitor interaction thermodynamics; (ii) changes in protein stability on the introduction of site mutations; (iii) thermodynamic stability and kinetics of folding for secondary and supersecondary structures in aqueous and non-aqueous environments. Ternary complexes of dihydrofolate reductase, NADPH and congeners of trimethoprim will serve as a prototype system for detailed investigations of interaction thermodynamics in the presence of protein and inhibitor conformational flexibility. From these studies general methodology will be advanced and direct comparison with NMR measurements of ligand dynamics will be made. Secondly, we will study the system of mutants from bacteriophage T4 lysozyme (thr-157) to examine changes in structure and thermodynamic stability upon mutation. An atomic level basis for these changes will be sought by application of thermodynamic component analysis and protein dynamics. Finally, we will explore the underlying principles of structural stability of protein and peptides. Combined constrained dynamics and thermodynamic simulation methods will be used to calculate free energy, energy and entropy surfaces for the formation of folded motifs in polar and apolar environments. The performance of the research described will provide new and extended methodologies for use in the calculation of thermodynamic properties. It will also bring about advances in our understanding of the basic principles governing enzyme-inhibitor association, protein stability and secondary structure formation and stability.