Department of Chemical Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
J Chem Theory Comput. 2017 Feb 14;13(2):563-576. doi: 10.1021/acs.jctc.6b01049. Epub 2017 Jan 23.
Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations are widely used in enzyme simulation. Over ten convergence studies of QM/MM methods have revealed over the past several years that key energetic and structural properties approach asymptotic limits with only very large (ca. 500-1000 atom) QM regions. This slow convergence has been observed to be due in part to significant charge transfer between the core active site and the surrounding protein environment, which cannot be addressed by improvement of MM force fields or the embedding method employed within QM/MM. Given this slow convergence, it becomes essential to identify strategies for the most atom-economical determination of optimal QM regions and to gain insight into the crucial interactions captured only in large QM regions. Here, we extend and develop two methods for quantitative determination of QM regions. First, in the charge shift analysis (CSA) method, we probe the reorganization of electron density when core active site residues are removed completely, as determined by large-QM region QM/MM calculations. Second, we introduce the highly parallelizable Fukui shift analysis (FSA), which identifies how core/substrate frontier states are altered by the presence of an additional QM residue in smaller initial QM regions. We demonstrate that the FSA and CSA approaches are complementary and consistent on three test case enzymes: catechol O-methyltransferase, cytochrome P450cam, and hen eggwhite lysozyme. We also introduce validation strategies and test the sensitivities of the two methods to geometric structure, basis set size, and electronic structure methodology. Both methods represent promising approaches for the systematic, unbiased determination of quantum mechanical effects in enzymes and large systems that necessitate multiscale modeling.
混合量子力学-分子力学（QM/MM）模拟在酶模拟中被广泛应用。过去几年的十多项 QM/MM 方法收敛性研究表明，关键的能量和结构性质随着 QM 区域的增大（约 500-1000 个原子）逐渐趋近于渐近极限。这种缓慢的收敛性部分归因于核心活性位点与周围蛋白质环境之间的显著电荷转移，这不能通过改进 MM 力场或 QM/MM 中使用的嵌入方法来解决。鉴于这种缓慢的收敛性，确定最节省原子的确定最佳 QM 区域的策略以及深入了解仅在大 QM 区域中捕获的关键相互作用变得至关重要。在这里，我们扩展和开发了两种用于定量确定 QM 区域的方法。首先，在电荷转移分析（CSA）方法中，我们通过大 QM 区域 QM/MM 计算来探测核心活性位点残基完全去除时电子密度的重新组织。其次，我们引入了高度可并行化的福井位移分析（FSA），该方法确定了核心/底物前沿态如何通过在较小的初始 QM 区域中添加额外的 QM 残基而发生变化。我们证明 FSA 和 CSA 方法在三种测试酶：儿茶酚 O-甲基转移酶、细胞色素 P450cam 和鸡卵清白溶菌酶上是互补和一致的。我们还引入了验证策略，并测试了两种方法对几何结构、基组大小和电子结构方法的敏感性。这两种方法都代表了在需要多尺度建模的酶和大型系统中系统地、无偏地确定量子力学效应的有前途的方法。
