title: Case study on temperature-accelerated molecular dynamics simulation of ligand dissociation: inducer dissociation from the Lac repressor protein.
abstract: We studied ligand dissociation from the inducer-binding domain of the Lac repressor protein using temperature-accelerated molecular dynamics (TAMD) simulations. With TAMD, ligand dissociation could be observed within relatively short simulation time. This allowed many dissociation trajectories to be sampled. Under the adiabatic approximation of TAMD, all but one degree of freedom of the system were sampled from usual canonical ensembles at room temperature. Thus, meaningful statistical analyses could be carried out on the trajectories. A systematic approach was proposed to analyze possible correlations between ligand dissociation and fluctuations of various protein conformational coordinates. These analyses employed relative entropies, allowing both linear and nonlinear correlations to be considered. Applying the simulation and analysis methods to the inducer binding domain of the Lac repressor protein, we found that ligand dissociation from this protein correlated mainly with fluctuations of side-chain conformations of a few residues that surround the binding pocket. In addition, the two binding sites of the dimeric protein were dynamically coupled: occupation of one site by an inducer molecule could significantly reduce or slow down conformational dynamics around the other binding pocket.
authors.affiliation: School of Life Sciences, ‡Hefei National Laboratory for Physical Sciences at the Microscales, and §Hefei Institutes of Physical Science, Chinese Academy of Sciences, University of Science and Technology of China , 96 Jinzhai Road, Hefei, Anhui 230026, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D001665:Binding Sites; D019277:Entropy; D007544:Isopropyl Thiogalactoside / Q000737:chemistry*; D056968:Lac Repressors / Q000737:chemistry*; D008024:Ligands; D016014:Linear Models; D056004:Molecular Dynamics Simulation; D017711:Nonlinear Dynamics; D011485:Protein Binding; D013696:Temperature
chemical_list: D056968:Lac Repressors; D008024:Ligands; D007544:Isopropyl Thiogalactoside