含Mo/W的金属酶甲酸脱氢酶(FDH)是有效和选择性的天然催化剂,其在环境条件下可逆地将CO2转化为甲酸盐。在这项研究中,我们研究了更大的蛋白质环境对活性位点静电势（ESP）的影响。为了模拟酶环境，我们使用了经典分子动力学和多尺度量子力学（QM）/分子力学（MM）模拟的组合。我们利用电荷偏移分析来系统地构建QM区域，并通过评估核心活性位点与蛋白质环境之间的电荷转移程度来分析活性位点的电子环境。末端硫属元素配体对金属中心ESP的贡献很大，并且取决于硫属元素的身份，类似的,与O相比，Se和S末端硫属元素的负ESP较少，无论金属是Mo还是W。侧链的取向和辅因子的构象也会影响ESP，强调蛋白质动态波动采样的重要性。总的来说,我们的观察表明，末端硫属元素配体身份在FDH的酶活性中起着重要作用，建议合理的生物启发催化剂设计的机会。
The Mo/W-containing metalloenzyme formate dehydrogenase (FDH) is an efficient and selective natural catalyst that reversibly converts CO2 to formate under ambient conditions. 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 classical molecular dynamics and multiscale quantum-mechanical (QM)/molecular-mechanical (MM) simulations. We leverage charge shift analysis 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 similar, less negative ESPs for Se and S terminal chalcogens in comparison to O regardless of whether the metal is Mo or W. The orientation of the side chains and conformations of the cofactor also affect the ESP, 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, suggesting opportunities for a rational bioinspired catalyst design.
