EFFICIENT CHARACTERIZATION OF COLLECTIVE MOTIONS AND INTERRESIDUE CORRELATIONS IN PROTEINS BY LOW-RESOLUTION SIMULATIONS

A low-resolution model is used together with recently developed knowle dge-based potentials for exploring the dynamics of proteins. Configura tions are generated using a Monte Carlo/Metropolis scheme combined wit h a singular value decomposition technique (SVD). The approach is show n to characterize the cooperative motions in good detail, at least 1 o rder of magnitude faster than atomic simulations. Trajectories are par titioned into modes, and the slowest ones are analyzed to elucidate th e dominant mechanism of collective motions. Calculations performed for bacteriophage T4 lysozyme, a two-domain enzyme, demonstrate that the structural elements within each domain are subject to strongly coupled motions, whereas the motions of the two domains with respect to each other are strongly anticorrelated. This type of motion, evidenced by t he synchronous fluctuations of the domain centroids by up to +/-4.0 An gstrom in opposite directions, is comparable to the movements observed by recent spin-labeling experiments in solution. The potential of mea n force governing these fluctuations is shown to be anharmonic. The be ta-sheet region at the N-terminal domain and the helix E in the C-term inal domain are identified as regions important for mediating cooperat ive motions and, in particular, for the opening and closing of the act ive-site cleft between the domains. Residues Leu66-Phe67 in the centra l helix C stop the propagation of correlated motions between the domai ns. There is a correlation between the groups involved in highly coope rative motions revealed by simulations and the highly protected region s during unfolding measured by pulsed H/D exchange and 2-D NMR.