A long-term objective of this research is the development of theoretical methods to be used as general tools in the investigation of enzyme-substrate interactions, drug design and protein engineering. The specific problems to be addressed involve the further development of the stochastic boundary molecular dynamics simulation method and applications of this technique to study protein-ligand interactions in aqueous solution. Developments of the stochastic boundary molecular dynamics approach include: a) the development of a protein boundary force model which describes electrostatic effects from distant parts of the biopolymer, and b) the development of an analytical solvent boundary force which properly accounts for solvent dielectric effects. These methods are extremely important in providing the correct energetic and thermodynamic description of aqueous biopolymers. The stochastic boundary molecular dynamics method will then be employed to study the structure, dynamics, and thermodynamics of enzyme-inhibitor interactions for aqueous solutions of; benzamidine inhibited trypsin, with substituted benzamidines also being examined; and ternary complexes of dihydrofolate reductase, from chicken liver, nicotinamide-adenine dinucleotide phosphate and trimethoprim (including, benzyl-substituted varients of trimethoprim). Particular attention will be focused on the relative binding affinities between substituted inhibitors and the interactions of solvent with both enzyme and substrate.
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