ENERGETIC AND KINETIC ASPECTS OF MACROMOLECULAR ASSOCIATION - A COMPUTATIONAL STUDY OF LAMBDA-REPRESSOR-OPERATOR COMPLEXATION

A detailed molecular view of structural, thermodynamic and kinetic asp ects is essential for a clear understanding of macromolecular associat ion. We have recently assembled a force field to capture the energetic s of protein-DNA interactions in aqueous solution, and to provide a th ermodynamic and kinetic description of association in a computationall y expeditious manner. An application of this force field to a lambda r epressor-operator with a partitioning of the interaction energies on a subunit basis has revealed some interesting features. Hydrogen bondin g and van der Waals interactions of the turn-recognition helix-turn su bunit of the protein with the nucleic acid bases in the major groove a ppear to determine specificity in binding. Brownian dynamics simulatio ns were performed on several models for the lambda repressor-operator system to monitor some mechanistic aspects, of relevance to kinetics o f complexation. The calculated joint probability for a nonspecific ass ociation of protein and DNA, driven mostly by electrostatics, followed by a sliding of the protein to the active site (operator region) on t he DNA; a search in reduced dimensional configuration space accessible to the system, is much more than the probability of a three-dimension al diffusion of the protein to the active site. Implications of these results to protein-DNA recognition are analyzed and discussed.