The catalytic mechanism of DNA and RNA polymerases

DNA and RNA polymerases (Pols) catalyze nucleic acid biosynthesis in all domains of life, with implications for human diseases and health. Pols carry out nucleic acid extension through the addition of one incoming nucleotide trisphosphate at the 3′-OH terminus of the growing primer strand, at every catalytic cycle. Thus, Pol catalysis involves chemical reactions for nucleophile 3′-OH deprotonation and nucleotide addition, as well as major protein conformational motions and structural rearrangements for nucleotide selection, binding, and nucleic acid translocation to complete the overall catalytic cycle. In this respect, quantum and molecular mechanics simulations, integrated with experimental data, have advanced our mechanistic understanding of how Pols operate at the atomic level. This Perspective outlines how modern molecular simulations can further deepen our understanding of Pol catalytic reactions and fidelity, which may help in devising strategies for designing drugs and artificial Pols for biotechnological and clinical purposes.