Influence of the Greater Protein Environment on the Electrostatic Potential in Metalloenzyme Active Sites: the Case of Formate Dehydrogenase

Abstract

The Mo/W containing metalloenzyme formate dehydrogenase (FDH) is an efficient and selective natural catalyst which reversibly converts CO2 to formate under ambient conditions. A greater understanding of the role of the protein environment in determining the local properties of the FDH active site would enable rational bioinspired catalyst design. In this study, we investigate the impact of the greater protein environment on the electrostatic potential (ESP) of the active site. To model the enzyme environment, we used a combination of long-timescale classical molecular dynamics (MD) and multiscale quantum-mechanical/molecular-mechanical (QM/MM) simulations. We leverage the charge shift analysis method to systematically construct QM regions and analyze the electronic environment of the active site by evaluating the degree of charge transfer between the core active site and the protein environment. The contribution of the terminal chalcogen ligand to the ESP of the metal center is substantial and dependent on the chalcogen identity, with ESPs less negative and similar for Se and S terminal chalcogens than for O regardless of whether the Mo6+ or W6+ metal center is present. Our evaluation reveals that the orientation of the sidechains and ligand conformations will alter the relative trends in the ESP observed for a given metal center or terminal chalcogen, highlighting the importance of sampling dynamic fluctuations in the protein. Overall, our observations suggest that the terminal chalcogen ligand identity plays an important role in the enzymatic activity of FDH.

Mechanistic Insights into Substrate Positioning That Distinguish Non-heme Fe(II)/α-Ketoglutarate-Dependent Halogenases and Hydroxylases

“…Long-range interactions were accounted for by incorporating semi-empirical dispersion corrections (i.e., DFT-D3) with default Becke−Johnson damping. 86 To approximate the impact of the greater protein environment on the electrostatic potential of the cluster models, 87 the calculations were carried out with an implicit conductor-like polarizable continuum model (C-PCM) with epsilon set to 10. 88,89 During all QM calculations, the backbone atoms were frozen to maintain the overall structure observed in the selected centroids.…”

Mechanistic Insights Into Substrate Positioning Across Non-heme Fe(II)/alpha-ketoglutarate-dependent Halogenases and Hydroxylases

“…Long range interactions were accounted for by incorporating semiempirical DFT-D3 with default Becke-Johnson damping. 83 To approximate the impact of the greater protein environment on the electrostatic potential of the cluster models, 84 the calculations were carried out with implicit conductor-like polarizable continuum model (C-PCM) with epsilon set to 10. 85,86 During all QM calculations, the backbone atoms were frozen to maintain the overall structure observed in the selected centroids.…”

Formic Acid Dehydrogenation Using Noble-Metal Nanoheterogeneous Catalysts: Towards Sustainable Hydrogen-Based Energy

“…Typically, certain appropriate compounds have been selected because they have greater hydrogen content and can release hydrogen effectively at ambient conditions (temperature and pressure) by catalytic or non-catalytic methods. Examples of such compounds include hydrous hydrazine, metal amidoborates, metal borohydrides, ammonia borane, sodium borohydride and formic acid (HCOOH; FA) [27][28][29][30][31]. However, because of their poor kinetics for reversible hydrogen adsorption-desorption interactions, low intrinsic thermal conductivity, thermodynamic stability, toxicity, and high price, the practical applicability of several of these hydrogen storage compounds is greatly limited [32].…”