Efficient characterization of collective motions and interresidue correlations in proteins by low-resolution simulations

A low-resolution model is used together with recently developed knowledge-based potentials for exploring the dynamics of proteins. Configurations are generated using a Monte Carlo/Metropolis scheme combined with a singular value decomposition technique (SVD). The approach is shown to characterize the cooperative motions in good detail, at least 1 order of magnitude faster than atomic simulations. Trajectories are partitioned into modes, and the slowest ones are analyzed to elucidate the 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 the synchronous fluctuations of the domain centroids by up to +/-4.0 Angstrom in opposite directions, is comparable to the movements observed by recent spin-labeling experiments in solution. The potential of mean force governing these fluctuations is shown to be anharmonic. The beta-sheet region at the N-terminal domain and the helix E in the C-terminal domain are identified as regions important for mediating cooperative motions and, in particular, for the opening and closing of the active-site cleft between the domains. Residues Leu66-Phe67 in the central helix C stop the propagation of correlated motions between the domains. There is a correlation between the groups involved in highly cooperative motions revealed by simulations and the highly protected regions during unfolding measured by pulsed H/D exchange and 2-D NMR.