Development and Validation of the Quantum Mechanical Bespoke Protein Force Field

Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus, they neglect system-specific polarization. In this paper, we introduce a complete protein force field that is designed to be compatible with the quantum mechanical bespoke (QUBE) force field by deriving nonbonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are rederived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE nonbonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, is tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained, and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. With several avenues for further development, the use of system-specific nonbonded force field parameters is a promising approach for next-generation simulations of biological molecules.传统上，蛋白质等大分子的分子力学力场（molecular mechanics force field）参数均通过拟合小分子的实验物性进行标定，因而会忽略体系特异性极化效应。本文提出了一套完整的蛋白质力场，其设计目标是与量子力学定制力场（quantum mechanical bespoke, QUBE）兼容：通过直接从所研究的特定蛋白质的电子密度出发推导非键相互作用参数（nonbonded parameters）。本研究通过拟合量子力学二面角扫描（dihedral scans）数据，重新推导了蛋白质主链与侧链的主要扭转参数，以适配QUBE的非键相互作用参数。本研究提供了用于制备QUBE输入文件的配套软件。通过将一系列肽与蛋白质的构象偏好性与实验测定结果进行对比，验证了新型力场及所推导扭转参数的准确性。在二肽的分子动力学（molecular dynamics）模拟中，可获得准确的主链与侧链构象，其核磁共振（Nuclear Magnetic Resonance, NMR）J耦合误差与广泛使用的OPLS力场相当。在5种折叠蛋白质的模拟中，二级结构（secondary structure）整体得以保留，核磁共振J耦合误差与标准可迁移力场（transferable force field）相近；尽管在蛋白质的部分区域观测到了实验结构的些许偏离。尽管仍有多处可进一步优化的方向，但采用体系特异性非键相互作用力场参数，是面向下一代生物分子模拟的极具潜力的研究路径。