Development and Validation of the QUBE Protein Force Field
Development and Validation of the QUBE Protein Force Field
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DOI：
10.26434/chemrxiv.7565222.v2
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发表时间：
2019-05
期刊：
影响因子：
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通讯作者：
A. Allen;M. J. Robertson;M. Payne;Daniel Cole
中科院分区：
文献类型：
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作者：
A. Allen;M. J. Robertson;M. Payne;Daniel Cole
大分子（如蛋白质）的分子力学力场参数传统上适合再现小分子的实验性质，因此它们忽略了系统特异性极化。在本文中，我们通过直接从所研究的特定蛋白质的电子密度导出非键参数，引入了一个与量子力学定制（QUBE）力场兼容的完整蛋白质力场。通过拟合量子力学二面体扫描，重新推导了主骨架和侧链蛋白的扭转参数，以与QUBE非键参数兼容。提供了编写QUBE输入文件的软件。通过将一系列多肽和蛋白质的构象偏好与实验测量结果进行比较，验证了新力场和推导出的扭转参数的准确性。在二肽分子动力学模拟中获得了精确的主链和侧链构象，其核磁共振J偶联误差可与广泛使用的ops力场相媲美。在对五种折叠蛋白的模拟中，二级结构通常被保留，核磁共振J耦合误差与标准可转移力场相似，尽管在蛋白质的某些区域观察到一些实验结构的损失。随着进一步发展的几个途径，使用系统特定的非键合力场参数是下一代生物分子模拟的一种有前途的方法。
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 non-bonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are re-derived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE non-bonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, are 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 non-bonded force field parameters is a promising approach for next-generation simulations of biological molecules.