Water-Gated Proton Transfer Dynamics in Respiratory Complex i

Max E. Mühlbauer, Patricia Saura, Franziska Nuber, Andrea Di Luca, Thorsten Friedrich, Ville R.I. Kaila

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


The respiratory complex I transduces redox energy into an electrochemical proton gradient in aerobic respiratory chains, powering energy-requiring processes in the cell. However, despite recently resolved molecular structures, the mechanism of this gigantic enzyme remains poorly understood. By combining large-scale quantum and classical simulations with site-directed mutagenesis and biophysical experiments, we show here how the conformational state of buried ion-pairs and water molecules control the protonation dynamics in the membrane domain of complex I and establish evolutionary conserved long-range coupling elements. We suggest that an electrostatic wave propagates in forward and reverse directions across the 200 Å long membrane domain during enzyme turnover, without significant dissipation of energy. Our findings demonstrate molecular principles that enable efficient long-range proton-electron coupling (PCET) and how perturbation of this PCET machinery may lead to development of mitochondrial disease.

Original languageEnglish
Pages (from-to)13718-13728
Number of pages11
JournalJournal of the American Chemical Society
Issue number32
StatePublished - 12 Aug 2020


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