The influence of the lower axial nickel ligand on the catalytic mechanism of methyl-coenzyme M reductase: a QM cluster study.

Authors

Ingso Limbu, Elizabeth H Krenske

Published in

Organic & biomolecular chemistry. Oct 09, 2026. Epub Oct 09, 2026.

Abstract

Methyl-coenzyme M reductase (MCR) is the enzyme responsible for production of methane by microorganisms that live in the digestive tracts of ruminants and other anaerobic environments. The enzyme contains a nickel tetrapyrrole cofactor (cofactor F₄₃₀) that can exist in a number of oxidation states. Previous computational studies of the MCR reaction mechanism have utilised available X-ray structures of the inactive Ni(II) state. However, a recent study by Ragsdale et al. reported crystallographic characterisation of the active Ni(I) state. Here we explore how the new Ni(I) active-site details influence modelling of the reaction pathway. We focus on the (i) non-covalent interactions among the active-site residues, (ii) identity of the lower axial ligand, and (iii) sensitivity to the choice of density functional. We find that to capture the substrate-binding microenvironment, in particular the interactions of the key Tyr367 residue, it is beneficial to augment previous cluster models by including three conserved phenylalanine residues. Using this expanded model, the potential catalytic role of an active-site water molecule reported to lie in bonding distance of the Ni(I) site is explored. Our computations suggest that the water molecule is not strongly coordinated to Ni, and is displaced by Gln147 during methane formation. The mechanistic predictions are relatively robust across functionals, and a cost-effective estimate of the barrier is obtained with TPSSh-D4//r²SCAN-3c. Overall, these results provide support for the main conclusions of previous QM cluster studies of MCR, while also elucidating new mechanistic subtleties and providing a reference point for future evaluation of new mechanistic proposals.

PMID:
42853131
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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