Molecular Mechanism of Substrate Oxidation in Lytic Polysaccharide Monooxygenases: Insight from Theoretical Investigations

Abstract

Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes that today comprise a large enzyme superfamily, grouped into the distinct members AA9-AA17 (with AA12 exempted). The LPMOs have the potential to facilitate the upcycling of biomass waste products by boosting the breakdown of cellulose and other recalcitrant polysaccharides. The cellulose biopolymer is the main component of biomass waste and thus comprises a large, unexploited resource. The LPMOs work through a catalytic, oxidative reaction whose mechanism is still controversial. For instance, the nature of the intermediate performing the oxidative reaction is an open question, and the same holds for the employed co-substrate. Here we review theoretical investigations addressing these questions. The applied theoretical methods are usually based on quantum mechanics (QM), often combined with molecular mechanics (QM/MM). We discuss advantages and disadvantages of the employed theoretical methods and comment on the interplay between theoretical and experimental results.

A Conserved Second Sphere Residue Tunes Copper Site Reactivity in Lytic Polysaccharide Monooxygenases

“…The spin-coupled open-shell singlet minimum 1 IC2 is at −13.3 kcal/mol, with Cu–O and O–O distances of 1.90 and 2.63 Å respectively. The geometry of 3 IC2 at the triplet spin state is nearly identical to 1 IC2, and 2.7 kcal/mol more stable, which is in agreement with previous reports on computational modeling of the Cu­(II)-oxyl in LPMOs. ,,, …”

“…The postulated Cu­(II)-oxyl intermediate is generated by a barrierless hydrogen-atom transfer (HAT) in which the hydroxyl radical abstracts a hydrogen from the copper-bound hydroxide to form water. It is worth mentioning that other computational studies also have shown that this step has a small , or vanishing barrier, as pointed out by Hagemann and Hedegård . The spin-coupled open-shell singlet minimum 1 IC2 is at −13.3 kcal/mol, with Cu–O and O–O distances of 1.90 and 2.63 Å respectively.…”

“…It is worth mentioning that other computational studies also have shown that this step has a small 16,17 or vanishing 43 barrier, as pointed out by Hagemann and Hedegard. 67 The spin-coupled open-shell singlet minimum 1 IC2 is at −13.3 kcal/mol, with Cu−O and O−O distances of 1.90 and 2.63 Å respectively. The geometry of 3 IC2 at the triplet spin state is nearly identical to 1 IC2, and 2.7 kcal/mol more stable, which is in agreement with previous reports on computational modeling of the Cu(II)-oxyl in LPMOs.…”

“…The geometry of 3 IC2 at the triplet spin state is nearly identical to 1 IC2, and 2.7 kcal/mol more stable, which is in agreement with previous reports on computational modeling of the Cu(II)-oxyl in LPMOs. 16,17,43,67 Adopting compelling suggestions by Bissaro et al 17 that the fluorescence quenching upon reaction of Cu(I)-LPMO with H 2 O 2 is associated with the first electron transfer, i.e. formation of the Cu(II)-hydroxide and the hydroxyl, we focus on the first transition state to rationalize the effect of the Q164E mutation on the reoxidation rate of NcAA9C.…”

Recent Theoretical Insights into the Oxidative Degradation of Biopolymers and Plastics by Metalloenzymes

“…This powered computational analysis at the multiconfigurational perturbation theory (CASPT2) level to address the reliability of the DFT-predicted spin-state gaps [ 92 ]. All these high-level computational works have been very recently collected in an excellent and comprehensive review by Hagemann and Hedegård, hence we address the reader to [ 93 ] for details about LPMO electronic structure, mechanistic insights, and role of the Cu second coordination sphere seen from a computational perspective.…”