Framework model for DNA polymerases

Biochemistry. 2005 May 10;44(18):6877-88. doi: 10.1021/bi0477079.

Abstract

DNA polymerases are complex machines with both chemical and mechanical functions. Recent crystal structures, ensemble kinetics, and single-molecule investigations have helped to elucidate the main properties of several DNA polymerases, all of which share common structural elements and a common basic mechanism, despite wide variations in amino acid sequence. The framework model is intended to aid in the understanding of these common features (and differences). It defines a class of models that automatically incorporates most of what is known about DNA polymerases within a single theoretical structure so that it is easier to make comparisons between them and to generate detailed models for specific polymerases. The framework model has three main elements: (1) a set of four key variables that describe the important motions within the protein-DNA-nucleotide complex, (2) a complete set of conformational states for the protein-DNA-nucleotide system, and (3) an approximate potential energy surface that controls the motions and transition rates between states. As an example application, we use the general framework ideas to build a detailed model for the HIV reverse transcriptase that is consistent with existing data, and predicts force-velocity curves and stepping-statistics histograms that can be directly compared to experiment.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Computer Simulation*
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Humans
  • Models, Chemical*
  • Models, Molecular*
  • Nucleic Acid Synthesis Inhibitors
  • Structure-Activity Relationship

Substances

  • Nucleic Acid Synthesis Inhibitors
  • DNA-Directed DNA Polymerase