Molecular Mechanism, Dynamics, and Energetics of Protein-Mediated Dinucleotide Flipping in a Mismatched DNA: A Computational Study of the RAD4-DNA Complex

Journal of Chemical Information and Modeling
Kartheek Pitta, Marimuthu Krishnan

Abstract

DNA damage alters genetic information and adversely affects gene expression pathways leading to various complex genetic disorders and cancers. DNA repair proteins recognize and rectify DNA damage and mismatches with high fidelity. A critical molecular event that occurs during most protein-mediated DNA repair processes is the extrusion of orphaned bases at the damaged site facilitated by specific repairing enzymes. The molecular-level understanding of the mechanism, dynamics, and energetics of base extrusion is necessary to elucidate the molecular basis of protein-mediated DNA damage repair. The present article investigates the molecular mechanism of dinucleotide extrusion in a mismatched DNA (containing a stretch of three contiguous thymidine-thymidine base pairs) facilitated by Radiation sensitive 4 (RAD4), a key DNA repair protein, on an atom-by-atom basis using molecular dynamics (MD) and umbrella-sampling (US) simulations. Using atomistic models of RAD4-free and RAD4-bound mismatched DNA, the free energy profiles associated with extrusion of mismatched partner bases are determined for both systems. The mismatched bases adopted the most stable intrahelical conformation, and their extrusion was unfavorable in RAD4-free mismat...Continue Reading

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Citations

Feb 13, 2020·Nucleic Acids Research·Abhinandan PanigrahiMarimuthu Krishnan

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