title: The control of the discrimination between dNTP and rNTP in DNA and RNA polymerase.
abstract: Understanding the origin of discrimination between rNTP and dNTP by DNA/RNA polymerases is important both for gaining fundamental knowledge on the corresponding systems and for advancing the design of specific drugs. This work explores the nature of this discrimination by systematic calculations of the transition state (TS) binding energy in RB69 DNA polymerase (gp43) and T7 RNA polymerase. The calculations reproduce the observed trend, in particular when they included the water contribution obtained by the water flooding approach. Our detailed study confirms the idea that the discrimination is due to the steric interaction between the 2'OH and Tyr416 in DNA polymerase, while the electrostatic interaction is the source of the discrimination in RNA polymerase. Proteins 2016; 84:1616-1624. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California, 90089-1062.
authors.forename: Hanwool
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California, 90089-1062. warshel@usc.edu.
authors.forename: Arieh
authors.initials: A
authors.lastname: Warshel
mesh_terms: D001665:Binding Sites; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry* / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D012265:Ribonucleotides / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D013379:Substrate Specificity; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry*
chemical_list: D015226:Dinucleoside Phosphates; D012265:Ribonucleotides; D014764:Viral Proteins; D014867:Water; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase; C463461:bacteriophage RB69 DNA polymerase
keywords: DNA polymerase; RNA polymerase; enzyme catalysis; free energy perturbation; internal water in proteins; sugar selectivity