Unified Structural, Dynamical and Energetic Perspectives on DNA Replication/Repair

High fidelity DNA polymerases perform the crucial task of DNA replication and repair, preserving the integrity of the genomic imprint in organisms. These enzymes have evolved over hundreds of thousands of years to perform accurate (1 error per million operations) and efficient (∼100-1000 base pairs synthesized per second) DNA synthesis. I will review our recent computational work on the bacillus fragment, a typical high fidelity polymerase, and present atomistic level insights on two important issues: (1) the mechanism by which high fidelity polymerases selectively catalyze the incorporation of nucleotides into a DNA strand, and (2) the failure of the replication/repair machinery in the event of oxidative damage to DNA. A new concept involving the coupling of slow delocalized DNA-polymerase motions to catalysis will be introduced. I will invoke this concept to rationalize some enigmatic results from force spectroscopy experiments and to make experimentally testable predictions. New ideas and concepts emerging from this work have broad implications for the study of biomolecular function and for nano-bio science.