Computer Simulations of Protein Functions: Searching for the Molecular Origin of the Replication Fidelity of DNA Polymerases

The use of computers to simulate the functions of complex biological macromolecules is essential to achieve a microscopic description of biological processes and to model and interpret experimental data. Here we apply theoretical computational approaches to investigate the fidelity of T7 DNA polymer...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-05, Vol.102 (19), p.6819-6824
Main Authors: Florián, Jan, Goodman, Myron F., Warshel, Arieh, Berne, Bruce J.
Format: Article
Language:English
Subjects:
Active sites
Base Pairing
Binding Sites
Biochemistry
Catalysis
Chemical Theory and Computation Special Feature
Chemicals
Computational Biology - methods
Computer Simulation
Coordinate systems
DNA
DNA - chemistry
DNA-Directed DNA Polymerase - chemistry
Enzymes
Free energy
Hot Temperature
Hydrogen-Ion Concentration
Hydrolysis
Ions
Kinetics
Ligands
Macromolecular Substances - chemistry
Magnesium - chemistry
Models, Molecular
Nucleic Acid Conformation
Nucleotides
Nucleotides - chemistry
Physical Sciences
Protein Conformation
Proteins - chemistry
Ratios
Software
Structure-Activity Relationship
Thermodynamics
Trajectories
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Summary:The use of computers to simulate the functions of complex biological macromolecules is essential to achieve a microscopic description of biological processes and to model and interpret experimental data. Here we apply theoretical computational approaches to investigate the fidelity of T7 DNA polymerase, divided into discrete steps that include contributions from substrate binding, pKashifts, and rate constants for the PO bond-breaking and bond-making processes. We begin by defining the discrimination between right and wrong nucleotides in terms of the free energy landscape for the dNMP incorporation reaction. We then use the linear response approximation and the empirical valence bond methods to obtain converging results for the contribution of the binding and chemical steps to the overall fidelity. These approaches are successful in reproducing general trends in the observed polymerase incorporation fidelity. The calculations demonstrate the potential for further integration of theoretical and experimental studies to analyze high- and low-fidelity DNA polymerases.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0408173102