Low-barrier hydrogen bond powers long-range radical transfer in the metal-free ribonucleotide reductase

• 成果类型: Article
• 署名作者: Sirohiwal, Abhishek; John, Juliane; Kutin, Yury; Kumar, Rohit; Baserga, Federico; Srinivas, Vivek; Lebrette, Hugo; Poverlein, Maximilian C.; Gamiz-Hernandez, Ana P.; Heberle, Joachim; Kasanmascheff, Muge; Hogbom, Martin; Kaila, Ville R. I.
• 署名单位: Stockholm University; Indian Institute of Science (IISC) - Bangalore; Dortmund University of Technology; Free University of Berlin; Universite de Toulouse (EPE); Centre National de la Recherche Scientifique (CNRS); Communaute d'universites et etablissements de Toulouse (Comue)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2529856123
• 发表日期: 2026-05-12
• 页码: e2529856123
• 关键词: PCET; LBHB; quantum biology; qm/mm; XFEL; COUPLED ELECTRON-TRANSFER; protein; resonance; PATHWAY; chemistry; transport; DYNAMICS; UNMASKS; complex

摘要

Ribonucleotide reductases (RNRs) catalyze the conversion of ribonucleotide (RNA) to deoxyribonucleotide (DNA) building blocks initiated by a long-range (>30 & Aring;) proton-coupled electron transfer (PCET) by mechanistic principles that remain much debated. By combining multiscale quantum and classical simulations with directed mutagenesis, X-ray crystallography, and vibrational and electron paramagnetic resonance spectroscopy, we elucidate here the molecular principles underlying how metal-free RNRs initiate the long-range PCET process by creating a highly stable 3,4-dihydroxyphenylalanine (DOPA) initiator radical. We show that DOPA center dot is redox-tuned by a low-barrier hydrogen bond (LBHB), with a delocalized proton that provides the catalytic power for the ribonucleotide reduction. We find that the LBHB couples to an extended hydrogen-bonded network, with distant mutations resulting in the loss of radical formation, and providing key molecular insight into the long-range radical transport mechanism in RNRs. On a general level, our findings support the direct involvement of LBHB in protein chemistry and the importance of quantum effects in enzyme catalysis.