THEORETICAL STUDIES ON THE DYNAMIC ASPECTS OF MACROMOLECULAR FUNCTION

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In this reporting period, four papers appeared in print dealing with (1) the decomposition of free energies (2) the theory and simulation of the rate of diffusion influenced chemical reaction (3) the relationship between first passage times, correlation functions and reaction rates and (4) the influence of high intensity laser pulses on fluorescence quenching. These will now be briefly described in turn. The problem of decomposing the total free energy of binding of a ligand to a protein into electrostatic Van der Waals etc. components has recently been a subject of great interest and controversy. We have been able to show that by expressing the free energy perturbation expansion in terms of temperature derivatives of the mean energy, a natural and useful decomposition of the free energy into components corresponding to each term in the Hamiltonian can be obtained. Many biological processes such as ligand binding to receptors, enzyme-substrate complex formation, protein DNA association, can often be described as diffusion influenced reactions. The rate of such reactions can only be obtained analytically for idealized (and unrealistic) models. We have developed a comprehensive theoretical framework to treat these reactions which leads to novel and efficient ways of obtaining the rates using Brownian dynamics computer simulations. A fundamental problem in chemical kinetics is how to calculate the rate of unimolecular reactions (such as isomerization) from the microscopic dynamics. Over the years several alternate definitions were proposed based on the theory of first passage times for irreversible processes and on the equilibrium fluctuations of certain quantities as determined by correlation functions. We have been able to find a rigorous relationship between these seemingly different approaches that clarify the circumstances under which they are equivalent. Finally, we have been able to solve the controversial and long outstanding problem of how one should theoretically treat excitation pulses in fluorescence quenching experiments. Our work indicates how such experiments should be correctly interpreted.