The long term objective of this proposal is to develop and implement state-of-the-art computer simulation software techniques including molecular dynamics, molecular mechanics, normal mode analysis, and interactive graphics analysis into an integrated system to attack problems in protein design. The ability to understand, guide, and accurately simulate the effects of modern recombinant DNA techniques applied to the engineering of proteins represents a significant contribution to protein engineering technology. To this end, phase I objectives are 1) further develop and implement existing molecular mechanics/dynamics package on the STAR ST-100, a powerful new generation array processor to enhance computational efficiency, 2) develop new data analysis and simulation algorithms to address specific protein design needs, and 3) conduct a preliminary study of structural and energetic consequences of mutagenesis experiments carried out on trypsin in the laboratory of Professor R. Fletterick, in order to test and refine the techniques. Specific phase I goals are 1) achieve a 60-80 fold speed enhancement of the software relative to a VAX 11/780, 2) complete a software interface between theoretical simulation and graphics packages, 3) set up the trypsin system and calculate the structure, energetics, and ligand binding affinity for various ligands of this protein, and 4) compare these predictions to experimental results. Phase II research will include extensive applications to evaluate the structural, energetic and ligand binding properties of several trypsin mutants as well as the development of more sophisticated analysis and simulations capabilities (such as free energy and entropy) and the development of a scientist friendly program interface. Our primary commercial objective for this research is to license these proven software tools and expertise to the chemical and pharmaceutical industries.
