A multifaceted research program is being directed at developing the capacity to make quantitative predictions on the structure and reactivity of biomolecular systems. The theoretical approach centers on computer similations at the atomic level using Monte Carlo statistical mechanics and molecular dynamics. A key element in the success of the computations is the need for potential functions that properly describe the interatomic interactions in the modeled systems. A complete set of such functions is being developed for representation of proteins and nucleic acids in their native environment. Parameterization includes results of high-level, ab initio quantum mechanics calculations and, most importantly, reproduction of experimental structural and thermodynamic data for pure organic liquids and aqueous solutions. Application and testing on biochemical systems will cover a range of complexity from oligopeptides to enzymes. A major thrust will be studies of the structures and binding characteristics of the third domains of avian ovomucoids. Many biophysical data are available on these serine protease inhibitors including over 100 sequences, several x-ray structures, and binding constants with a series of enzymes. Structures will be calculated for interesting sequence variants and hydrolyzed inhibitors in water prior to diffraction studies. Calculations of relative binding constants are also planned using the latest free energy techniques. In addition, amphiphilic interfacial systems will be modeled to gain insight into the structure of biological membranes. Initial studies will include simulations of biphasic alcohol/water systems as well as monolayers of alcohols on water. Subsequent work on the interface between water and phospholipid head groups will lead to simulations of full phospholipid bilayers.
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