Energetic and kinetic aspects of macromolecular association: computational study of X repressor-operator complexation

Abstract

A detailed molecular view of structural, thermodynamic and kinetic aspects is essential for a clear understanding of macromolecular association. We have recently assembled a force field to capture the energetics of protein-DNA inter- actions in aqueous solution, and to provide a thermodynamic and kinetic description of association in a computationally expeditious manner. An application of this force field to a X repressor-operator with a partitioning of the interaction energies on a subunit basis has revealed some interesting features. Hydrogen bonding and van der Waals interactions of the turn-recognition helix-turn subunit of the protein with the nucleic acid bases in the major groove appear to determine specificity in binding. Brownian dynamics simulations were performed on several models for the X repressor-operator system to monitor some mechanistic aspects, of relevance to kinetics of B mplexation. The calculated joint probability for a nonspecific association of protein and DNA, driven mostly by electrostatics, followed by a sliding of the protein to the active site (operator region) on the DNA, a search in reduced dimensional configuration space accessible to the system, is much more than the probability of a three-dimensional diffusion of the protein to the active site. Implications of these results to protein-DNA recognition are analyzed and discussed.