title: Nonequilibrium Relaxation of Conformational Dynamics Facilitates Catalytic Reaction in an Elastic Network Model of T7 DNA Polymerase.
abstract: Nucleotide-induced conformational closing of the finger domain of DNA polymerase is crucial for its catalytic action during DNA replication. Such large-amplitude molecular motion is often not fully accessible to either direct experimental monitoring or molecular dynamics simulations. However, a coarse-grained model can offer an informative alternative, especially for probing the relationship between conformational dynamics and catalysis. Here we investigate the dynamics of T7 DNA polymerase catalysis using a Langevin-type elastic network model incorporating detailed structural information on the open conformation without the substrate bound. Such a single-parameter model remarkably captures the induced conformational dynamics of DNA polymerase upon dNTP binding, and reveals its close coupling to the advancement toward transition state along the coordinate of the target reaction, which contributes to significant lowering of the activation energy barrier. Furthermore, analysis of stochastic catalytic rates suggests that when the activation energy barrier has already been significantly lowered and nonequilibrium relaxation toward the closed form dominates the catalytic rate, one must appeal to a picture of two-dimensional free energy surface in order to account for the full spectrum of catalytic modes. Our semiquantitative study illustrates the general role of conformational dynamics in achieving transition-state stabilization, and suggests that such an elastic network model, albeit simplified, possesses the potential to furnish significant mechanistic insights into the functioning of a variety of enzymatic systems.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.|Graduate Program in Biophysics, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Ziqing W
authors.initials: ZW
authors.lastname: Zhao
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.|Graduate Program in Biophysics, Harvard University , Cambridge, Massachusetts 02138, United States.|Biodynamic Optical Imaging Center (BIOPIC), Peking University , Beijing 100871, P. R. China.
authors.forename: X Sunney
authors.initials: XS
authors.lastname: Xie
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), Peking University , Beijing 100871, P. R. China.|Beijing International Center for Mathematical Research (BICMR), Peking University , Beijing 100871, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ge
mesh_terms: D055162:Biocatalysis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013269:Stochastic Processes
chemical_list: C034970:bacteriophage T7 induced DNA polymerase; D004259:DNA-Directed DNA Polymerase