Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

Abstract

Quantum mechanics/molecular mechanics calculations are employed to assign previously recorded experimental spectroscopic signatures of the intermediates occurring during the photo-induced repair of (6-4) photolesions by photolyases to specific molecular structures. Based on this close comparison of experiment and theory it is demonstrated that the acting repair mechanism involves proton transfer from the protonated His365 to the N3′ nitrogen of the lesion, which proceeds simultaneously with intramolecular OH transfer along an oxetane-like transition state.

Insights into Light‐driven DNA Repair by Photolyases: Challenges and Opportunities for Electronic Structure Theory

“…In addition, by means of pulsed electron‐nuclear double‐resonance spectroscopy, researcher characterized selected proton hyperfine couplings and illustrated that the repair activity is decreased when deuterium oxide is used as a solvent. Thus, the majority of researchers seem to agree that the mechanisms invoking proton transfer from the nearby histidines are crucial and open up an alternative pathway for repair .…”

“…3. The proton transfer‐steered mechanism in which PT from the protonated His365 to the N3′ nitrogen of the 3′‐T proceeds synchronically with formation of an oxetane‐like transition state involving intermediates IIIa and IIIb (Fig. ).…”

“…The first crystal structure of the isolated enzyme inspired many theoreticians to hypothesize possible mechanisms of these processes . Similar to their role in many other fields, experiment and theory together eventually led to comprehensive picture of the photoinduced processes of DNA photolyases . The present status of experimental and theoretical studies on the various steps involved in the repair mechanism of DNA photolyases (both CPD and 6‐4) has been already reviewed by several authors , including us, and many aspects of the mechanism have been clarified.…”

“…However, one additionally needs robust and predictive computational tools to interpret experimental observations and to develop a detailed mechanistic picture of the DNA photolyase repair cycle, at an atomic or even electronic structure level. The first crystal structure of the isolated enzyme inspired many theoreticians to hypothesize possible mechanisms of these processes . Similar to their role in many other fields, experiment and theory together eventually led to comprehensive picture of the photoinduced processes of DNA photolyases .…”

Sequential electron transfer governs the UV-induced self-repair of DNA photolesions

“…3 , 4 Despite the existence of repairing machinery, DNA photolesions are a common cause of skin cancer 1 , 5 – 7 and the mechanistic details of their formation and repair have been attracting significant attention involving both experimental and theoretical studies. 8 – 17 …”