用量子力学的方法描述蛋白内的化学相互作用无疑是最为精确的。笔者着力发展了EE-GMFCC（静电场作用下推广的带共轭帽的分子碎片化方法）分块量子化学计算方法，能够精确计算出蛋白质大分子在真空中的电子结构，这个方法是完全线性标度的，并且高度并行化。本项目在继承以前工作的基础上，重点开展以下四方面的工作:1)发展EE-GMFCC与溶剂化效应（PCM模型）相结合的方法以精确的全量子计算生物大分子的溶解能。2）在EE-GMFCC方法所计算的蛋白质电子结构势能面的基础上，推导出解析的能量梯度从而优化蛋白的结构，并运用分块的全量子化学方法计算蛋白的热力学性质。3）用全量子的方法计算蛋白-药物分子相互作用体系在溶液中的结合自由能。挖掘在传统分子力场方法下被忽略的静电极化效应和电子结构的重排能。4）运用自动分块的全量子化学方法AF-QM/MM来模拟生物大分子在溶液中的核磁共振谱。

An electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method is developed for efficient linear-scaling quantum mechanical (QM) calculation of protein energy. The EE-GMFCC approach has been applied for proteins at the levels of Hartree-Fock (HF)，density functional theory (DFT) and second-order many-body perturbation theory (MP2), showing only a few kcal/mol deviation from the corresponding full system result. The EE-GMFCC method is linear-scaling with a low prefactor and trivially parallel. The EE-GMFCC method will be employed to following applications: 1) By combining with the polarizable continuum solvation model (PCM), calculate the solvation energy of protein in solution. 2) Derive the analytical atomic gradient for proteins based on the EE-GMFCC potential. Optimize the geometry of protein and calculate the thermodynamic properties of proteins. 3) Calculate the protein-ligand binding free energy in solution based on the EE-GMFCC approach and verify the importance of the electronic polarization effect and wavefunction distortion energy for protein-ligand binding systems in solution, which are ignored by traditional molecular force field. 4) Simulate the nuclear magnetic resonance (NMR) spectra of proteins based on the AF-QM/MM (Automated fragmentation-quantum mechanics/molecular mechanics) method (including NMR chemical shift, NMR chemical shift anisotropy and spin-spin coupling constant).