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Thermal Motions of the E. Coli Glucose-Galactose Binding Protein Studied Using Well-Sampled Semi-Atomistic Simulations

The E. coli glucose-galactose chemosensory receptor is a 309 residue, 32 kDa protein consisting of two distinct structural domains. In this computational study, we studied the protein's thermal fluctuations, including both the large scale interdomain movements that contribute to the receptor's mechanism of action, as well as smaller scale motions, using two different computational methods. We employ extremely fast, "semi-atomistic" Library-Based Monte Carlo (LBMC) simulations, which include all backbone atoms but "implicit" side chains. Our results were compared with previous experiments and an all-atom Langevin dynamics simulation. Both LBMC and Langevin dynamics simulations were performed using both the apo and glucose-bound form of the protein, with LBMC exhibiting significantly larger fluctuations. The LBMC simulations are also in general agreement with the disulfide trapping experiments of Careaga & Falke (JMB, 1992; Biophys. J., 1992), which indicate that distant residues in the crystal structure (i.e. beta carbons separated by 10 to 20 angstroms) form spontaneous transient contacts in solution. Our simulations illustrate several possible "mechanisms" (configurational pathways) for these fluctuations. We also observe several discrepancies between our calculations and experiment. Nevertheless, we believe that our semi-atomistic approach could be used to study the fluctuations in other proteins, perhaps for ensemble docking, or other analyses of protein flexibility in virtual screening studies.