Here, we describe a novel and general mechanism for nucleic acid polymerization catalyzed by DNA/RNA Polymerases. Importantly, the enzymatic polymerization of DNA and RNA is the basis for genetic inheritance for all living organisms. It is catalyzed by the DNA/RNA polymerase (Pol) superfamily. In this study, we reveal that the incoming nucleotide substrate always forms an H-bond between its 3-OH and beta phosphate moieties upon formation of the Michaelis complex. This previously unrecognized H-bond implies a novel self-activated mechanism (SAM) for efficient polymerase catalysis, which is based on the identification of an evolutionary convergence to preserve a key enzymatic structural element in all the available X-ray structures of DNA/RNA polymerases. Importantly, SAM is characterized by a synergistic interplay between chemical (i.e., nucleophile formation and nucleotide addition) and physical (i.e., nucleic acid translocation) steps to form an elegant closed-loop cycle for efficient Pols catalysis. Our proposed mechanism is corroborated via classical MD and ab initio Car-Parrinello QM/MM simulations on a specific Pol, the human DNA polymerase-η (Pol-η). This enzyme is involved in repairing damaged DNA, and it is a promising drug target to treat skin carcinogenesis and overcome cancer drug resistance. Remarkably, the structural conservation of DNA and RNA Pols supports the possible extension of SAM to Pol enzymes from the three domains of life.

Multiscale simulations to elucidate enzymatic processing of DNA and RNA

253rd National Meeting (2017)

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