Cheminformatic quantum mechanical enzyme model design: A catechol-O-methyltransferase case study
Cheminformatic quantum mechanical enzyme model design: A catechol-O-methyltransferase case study
复制标题
化学信息量子力学酶模型设计：儿茶酚-O-甲基转移酶案例研究
DOI：
10.1016/j.bpj.2021.07.029
复制
发表时间：
2021
影响因子：
3.4
通讯作者：
DeYonker, Nathan J.
中科院分区：
文献类型：
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作者：
Summers, Thomas J.;Cheng, Qianyi;Palma, Manuel A.;Pham, Diem-Trang;Kelso, Dudley K.;Webster, Charles Edwin;DeYonker, Nathan J.
为了用量子力学（QM）准确地模拟酶活性位点的内部工作，不仅必须将反应性物种包括在模型中，还必须包括参与构建微环境的重要周围残留物、溶剂或辅酶。我们的实验室一直在开发残基相互作用网络残基分析（RINRUS）工具包，利用原子间的接触网络信息进行自动化，合理的残基选择和QM簇模型生成。从儿茶酚-O-甲基转移酶的X-射线晶体结构出发，利用RINRUS建立了一系列的QM-簇模型。对550个模型进行了甲基转移反应的反应物、产物和过渡态的计算，并将所得的活化自由能和反应自由能用于评估模型的收敛性。RINRUS设计的模型只有200-300个原子。RINRUS将作为改进和自动化的基于化学信息学的酶模型设计的基石。
To accurately simulate the inner workings of an enzyme active site with quantum mechanics (QM), not only must the reactive species be included in the model but also important surrounding residues, solvent, or coenzymes involved in crafting the microenvironment. Our lab has been developing the Residue Interaction Network Residue Selector (RINRUS) toolkit to utilize interatomic contact network information for automated, rational residue selection and QM-cluster model generation. Starting from an x-ray crystal structure of catechol-O-methyltransferase,RINRUSwas used to construct a series of QM-cluster models. The reactant, product, and transition state of the methyl transfer reaction were computed for a total of 550 models, and the resulting free energies of activation and reaction were used to evaluate model convergence.RINRUS-designed models with only 200–300 atoms are shown to converge.RINRUSwill serve as a cornerstone for improved and automated cheminformatics-based enzyme model design.