Klvaňa, Martin Jeřábek, Petr Goodman, Myron F. Florián, Jan An Abridged Transition State Model To Derive Structure, Dynamics, and Energy Components of DNA Polymerase β Fidelity We show how a restricted reaction surface can be used to facilitate the calculation of biologically important contributions of active site geometries and dynamics to DNA polymerase fidelity. Our analysis, using human DNA polymerase beta (pol β), is performed within the framework of an electrostatic linear free energy response (EFER) model. The structure, dynamics, and energetics of pol β-DNA–dNTP interactions are computed between two points on the multidimensional reaction free energy surface. “Point 1” represents a ground state activation intermediate (GSA), which is obtained by deprotonating the terminal 3′OH group of the primer DNA strand. “Point 2” is the transition state (PTS) for the attack of the 3′O<sup>–</sup> (O<sub>nuc</sub>) on the P<sub>α</sub> atom of dNTP substrate, having the electron density of a dianionic phosphorane intermediate. Classical molecular dynamics simulations are used to compute the geometric and dynamic contributions to the formation of right and wrong O<sub>nuc</sub>–P chemical bonds. Matched dCTP·G and mismatched dATP·G base pairs are used to illustrate the analysis. Compared to the dCTP·G base pair, the dATP·G mismatch has fewer GSA configurations with short distances between O<sub>nuc</sub> and P<sub>α</sub> atoms and between the oxygen in the scissile P–O bond (O<sub>lg</sub>) and the nearest structural water. The thumb subdomain conformation of the GSA complex is more open for the mismatch, and the H-bonds in the mispair become more extended during the nucleophilic attack than in the correct pair. The electrostatic contributions of pol β and DNA residues to catalysis of the right and wrong P–O<sub>nuc</sub> bond formation are 5.3 and 3.1 kcal/mol, respectively, resulting in an 80-fold contribution to fidelity. The EFER calculations illustrate the considerable importance of Arg183 and an O<sub>lg</sub>-proximal water molecule to pol β fidelity. electron density;energy response;energy surface;OH;PTS;DNA Polymerase β FidelityWe show;thumb subdomain conformation;bond;site geometries;Onuc;transition state;DNA polymerase beta;P α atoms;primer DNA strand;dianionic phosphorane;contribution;Abridged Transition State Model;Arg 183;pol β;dNTP substrate;DNA residues;nucleophilic attack;pol β fidelity;EFER calculations;GSA configurations;reaction surface;Derive Structure;ground state activation;DNA polymerase fidelity;P α atom;Energy Components;dynamics simulations 2011-08-16
    https://acs.figshare.com/articles/journal_contribution/An_Abridged_Transition_State_Model_To_Derive_Structure_Dynamics_and_Energy_Components_of_DNA_Polymerase_Fidelity/2623192
10.1021/bi200790s.s001