Convergence in determining enzyme functional descriptors across Kemp eliminase variants.
Convergence in determining enzyme functional descriptors across Kemp eliminase variants.
复制标题
确定 Kemp 消除酶变体的酶功能描述符的趋同性。
DOI：
10.1088/2516-1075/acad51
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yang,ZhongyueJ
中科院分区：
文献类型：
--
作者：
Jiang,Yaoyukun;Stull,SebastianL;Shao,Qianzhen;Yang,ZhongyueJ
分子模拟已被广泛用于加速生物催化发现。来自分子模拟的酶功能描述符已被用来指导有益的酶突变体的搜索。然而，理想的活性位点区域大小计算的描述符在多个酶的变体仍然未经测试。在这里，我们进行了收敛测试的动态派生和静电的描述符上的18个肯普消除酶的变种在6个活性位点的区域与不同的边界距离基板。所测试的描述符包括活性位点区域的均方根偏差、基质与活性位点之间的溶剂可及表面积比以及电场（EF）在断裂C-H键上的投影。所有的描述符进行了评价，使用分子力学方法。为了理解电子结构的影响，还使用量子力学/分子力学方法评估EF。计算了18种肯普消除酶变体的描述符值。使用斯皮尔曼相关矩阵来确定区域大小条件，在该条件下，区域边界的进一步扩展基本上不改变描述符值的排名。我们观察到，蛋白质动力学衍生的描述符，包括RMSD活性位点和SASA比，收敛在距离底物5 μ m的截止距离。静电描述子，EF C-H，收敛在6 μ m使用截断酶模型的分子力学方法和4 μ m使用量子力学/分子力学方法与整个酶模型。这项研究作为一个未来的参考，以确定酶工程的预测建模的描述符。
Molecular simulations have been extensively employed to accelerate biocatalytic discoveries. Enzyme functional descriptors derived from molecular simulations have been leveraged to guide the search for beneficial enzyme mutants. However, the ideal active-site region size for computing the descriptors over multiple enzyme variants remains untested. Here, we conducted convergence tests for dynamics-derived and electrostatic descriptors on 18 Kemp eliminase variants across six active-site regions with various boundary distances to the substrate. The tested descriptors include the root-mean-square deviation of the active-site region, the solvent accessible surface area ratio between the substrate and active site, and the projection of the electric field (EF) on the breaking C–H bond. All descriptors were evaluated using molecular mechanics methods. To understand the effects of electronic structure, the EF was also evaluated using quantum mechanics/molecular mechanics methods. The descriptor values were computed for 18 Kemp eliminase variants. Spearman correlation matrices were used to determine the region size condition under which further expansion of the region boundary does not substantially change the ranking of descriptor values. We observed that protein dynamics-derived descriptors, including RMSD active_site and SASA ratio, converge at a distance cutoff of 5 Å from the substrate. The electrostatic descriptor, EF C–H, converges at 6 Å using molecular mechanics methods with truncated enzyme models and 4 Å using quantum mechanics/molecular mechanics methods with whole enzyme model. This study serves as a future reference to determine descriptors for predictive modeling of enzyme engineering.