THEORETICAL STUDIES ON THE DYNAMIC ASPECTS OF MACROMOLECULAR FUNCTION

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The kinetics of the geminate rebinding of nitric oxide following photodissociation to myoglobin was simulated using the technique of molecular dynamics. The kinetic progress curve, obtained by averaging 100 trajectories, could be well reproduced by a simple model of a Langevin particle moving in a potential of mean force calculated from nonreactive trajectories. The rate of escape from the energy well adjacent to the heme was in good agreement with the value calculated from experimental data, suggesting that a multiple-well model provides a plausible explanation for the nonexponential rebinding kinetics. A Brownian dynamics algorithm, originally devised for calculating diffusion-controlled reaction rates, has been adapted to calculate the transalational hydrodynamic friction (i.e., the reciprocal of the diffusion coefficient) of objects with complex shapes. This work in effect exploits a deep analogy between two seemingly unrelated physical quantities, and leads to a novel and highly efficient way of calculating the diffusion coefficients of macromolecules. A theory has been developed for the electrophoresis of DNA molecules in microlithographically constructed synthetic gels consisting of an essentially two dimensional regular array of posts. Specifically, the average "unhooking" time for a DNA molecule that got hooked on a post to form a U-shaped structure was calculated. Good agreement was found between theory and experiment, indicating that one fundamental aspect of the mechanism of length fractionation can be fully understood on a microscopic level. An efficient algorithm developed in this laboratory to calculate the electrostatic properties of macromolecules has been applied to the cytochrome c-cytochrome peroxidase system to elucidate the influence of electrostatic interactions on redox potentials, the free energy of complex formation and the efficiency of electron transfer. In addition to successfully predicting the effect of mutations on those properties, these calculations revealed the structural basis of how the redox potential and the rate of election transfer is controlled by the protein environment.