The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

Despite the remarkable resistance of nucleic acid phosphodiester backbone to degradation affording genetic stability, P–O bond must be broken during DNA repair and RNA metabolism, among many other critical cellular processes. Nucleases are powerful enzymes that can enhance uncatalyzed rate cleavage by up ∼1017-fold. most well accepted hydrolysis mechanism involving two metals (MA2+ activate a water nucleophile MB2+ stabilize leaving group), experimental evidence suggests some nucleases use single metal facilitate chemical step, controversial concept in literature. The present perspective uses case studies four (I-PpoI, APE1, bacterial human EndoV) highlight how computational approaches ranging from quantum mechanical (QM) cluster models molecular dynamics (MD) simulations combined mechanics-molecular mechanics (QM/MM) calculations reveal atomic level details necessary understand nuclease this difficult chemistry. representative showcase different amino residues (e.g., histidine, aspartate) fulfill role first (MA2+) two-metal-mediated mechanisms. Nevertheless, differences active site architectures afford diversity single-metal-mediated terms metal–substrate coordination, metal, identities general base. greater understanding catalytic mechanisms obtained body work reviewed used further explore progression diseases associated with (mis)activity development novel applications such as disease diagnostics, gene engineering, therapeutics.

Language: Английский