Unraveling the Reaction Mechanism of Mo/Cu CO Dehydrogenase Using QM/MM Calculations

Abstract

Some microorganisms, like the aerobic soil bacteria, Oligotropha carboxidovorans, have the capability to oxidize the highly toxic atmospheric gas carbon monoxide (CO) into CO 2 through CO dehydrogenase enzymes, whose active site contains a bimetallic MoCu center. Over the last decades, a number of experimental and theoretical investigations were devoted to understanding the mechanism of CO oxidation and, in particular, the role of a very stable thiocarbonate intermediate that may be formed during the catalytic cycle. The occurrence of such an intermediate was reported to make the CO 2 release step kinetically difficult. In this work, by using an accurate QM/MM approach and energy refinement by means of the BigQM method, we were able to determine the role of such an intermediate and propose a novel mechanism for the oxidation of CO into CO 2 by Mo/Cu CO dehydrogenase. Surprisingly, we found that the detachment of CO 2 occurs directly from the product of the MoO nucleophilic attack reaction on the carbon of CO aided by the transient coordination of the active site glutamate to the Mo ion. The estimated activation barrier is in good agreement with the experimental one, while the thiocarbonate turned out to not interfere with the CO-oxidation catalytic cycle. The results highlight the importance of the environmental effects in the assembly of the molecular model and in the choice of the computational protocol. Our accurate modeling of the enzyme also allowed us to exclude the involvement of a frustrated Lewis pair in the CO-oxidation mechanism, which has recently been suggested based on an analysis of structural and electronic features of synthetic mimics of the Mo/Cu CO dehydrogenase active site.

Bimetallic Sites for Catalysis: From Binuclear Metal Sites to Bimetallic Nanoclusters and Nanoparticles

“…The Mo and Cu atoms are bridged by S, and Mo is considered as the site for performing the redox process (between Mo IV /Cu I and Mo VI /Cu I ), while Cu is responsible for the CO capture and catalytic turnover . After the oxidation of CO to CO 2 , the Mo VI site is regenerated by extracting oxygen from water . Solid catalysts made by mixed Cu-based oxide nanoparticles have been widely employed as excellent catalysts for CO oxidation, such as Cu–Mn mixed oxides, and the active sites in these solid catalysts are proposed to be associated with the Cu–O–Mn species, , which could also be considered as motifs as binuclear bimetallic sites in CO dehydrogenase.…”

“…250 After the oxidation of CO to CO 2 , the Mo VI site is regenerated by extracting oxygen from water. 251 Solid catalysts made by mixed Cu-based oxide nanoparticles have been widely employed as excellent catalysts for CO oxidation, such as Cu−Mn mixed oxides, and the active sites in these solid catalysts are proposed to be associated with the Cu−O−Mn species, 252,253 which could also be considered as motifs as binuclear bimetallic sites in CO dehydrogenase. The critical role of forming bridged M1−O−M2 species in mixed oxide catalysts for CO oxidation reaction has been validated by surface science study, in which the isolated Ni atoms deposited on CuO surface can catalyze the CO oxidation through the Eley−Rideal mechanism.…”

Impacts of QM region sizes and conformation numbers on modelling enzyme reactions: a case study of polyethylene terephthalate hydrolase

“…[23][24][25] This strategy is particularly suitable for understanding the catalytic mechanism of metalloenzymes, especially for enzymes containing variable valence metals (e.g., Fe, Co, Ni, Cr, and Mn). [26][27][28][29][30][31][32] However, there are emerging concerns that 500 or 1000 atoms should be considered for the QM region while this large size is still not routinely applied currently. [33][34][35][36] The third strategy employs high-level DFT/MM calculations while considering multiple enzyme conformations (multi-PES DFT/MM).…”

“…, Fe, Co, Ni, Cr, and Mn). 26–32 However, there are emerging concerns that 500 or 1000 atoms should be considered for the QM region while this large size is still not routinely applied currently. 33–36 The third strategy employs high-level DFT/MM calculations while considering multiple enzyme conformations (multi-PES DFT/MM).…”

Combining [MoVIO3] and [M0(CO)3] (M = Mo, Cr) Fragments within the Same Complex: Synthesis and Reactivity of the Single Oxo-Bridged Heterobimetallics Supported by Xanthene-Based Heterodinucleating Ligands

“… , CO is proposed to initially coordinate to the Cu­(I) site. , The carbonyl carbon is then attacked by the nucleophilic (basal) Mo­(VI)-oxo function, eventually forming CO 2 through a series of intermediates . While the general outline of the reaction mechanism has been established with a high degree of confidence using structural, spectroscopic, and computational studies, , some of the key mechanistic details are still lacking. The discernment of these details is crucial for the design of bioinspired CO oxidation and a CO 2 reduction molecular catalyst.…”