Biomolecular force fields: where have we been, where are we now, where do we need to go and how do we get there?
Biomolecular force fields: where have we been, where are we now, where do we need to go and how do we get there?
复制标题
DOI：
10.1007/s10822-018-0111-4
复制
发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Hagler, A. T.
中科院分区：
文献类型：
--
作者：
Dauber-Osguthorpe, Pnina;Hagler, A. T.
从这个角度，我们回顾了力场的理论和方法，以及它们在分子模拟中的有效性，从它们在20世纪下半叶开始，到本世纪末得到改进。我们检查体现在各种力场中的物理表示，它们的准确性和不足。在20世纪50年代和60年代的早期，人们首次引入傅立叶变换来分析振动光谱。随着计算机的出现，第一台分子力学机器计算很快问世。从最初的论文开始，人们就认识到，如果要获得有意义的计算结构和热力学性质，函数函数表示物理的准确性是至关重要的。我们讨论了Lifson以及后来的Allinger提出的严格的方法来推导分子函数，不仅获得了最佳的参数，而且揭示了物理表示中的不足，并改进了泛函形式来解释这种物理。在此背景下，评估价坐标之间的已知耦合以及耦合项对描述这种耦合的物理意义的重要性。回顾了早期引入的简化的、截断的函数，以允许模拟大分子系统，并对它们随后的改进进行了评估。我们深入研究了：氢键的重新公式的基础到其目前的描述；量子力学的早期引入到FF开发方法中，以计算部分电荷和转动势垒；晶体结构和高能观测提供的强大和丰富的信息，以推导和测试FF的所有方面，包括非键和分子内的功能形式；结合使用量子力学，以及结晶学和晶格能计算来推导转动势垒？以及：通过对QM能量面进行采样，或者通过计算数百种构型的能量，或者通过通过在表面上采样的能量、一阶和二阶导数来描述能量面，以及使用后者来探测物理表示的有效性、揭示缺陷和评估改进的函数形式，来获得QM FF的方法的发展和结果。研究表明，在使用不适当的扭角来表示离面变形时，缺陷的显著影响，以及用于非粘结相互作用的标准Lorentz-Berthelot组合规则，以及所给出的更准确的描述。最后，我们讨论了在推导第二代全原子版本的CHARMm，Amber和OPLS FF时所涉及的深入研究，以及这些研究中使用的广泛的可观测集合如何本着Lifson的精神，对这两种能力，但更重要的是所使用的对角线12-6-1 FF中的缺陷进行了表征。注意到这些论文中汇编的作为测试改进形式的基础的广泛的一组观测数据所作出的重大贡献。在下面的论文中，我们讨论了在上述研究之后的几年中所研究的在改进FF和物理表示方面的进展。
In this perspective, we review the theory and methodology of the derivation of force fields (FFs), and their validity, for molecular simulations, from their inception in the second half of the twentieth century to the improved representations at the end of the century. We examine the representations of the physics embodied in various force fields, their accuracy and deficiencies. The early days in the 1950s and 60s saw FFs first introduced to analyze vibrational spectra. The advent of computers was soon followed by the first molecular mechanics machine calculations. From the very first papers it was recognized that the accuracy with which the FFs represented the physics was critical if meaningful calculated structural and thermodynamic properties were to be achieved. We discuss the rigorous methodology formulated by Lifson, and later Allinger to derive molecular FFs, not only obtain optimal parameters but also uncover deficiencies in the representation of the physics and improve the functional form to account for this physics. In this context, the known coupling between valence coordinates and the importance of coupling terms to describe the physics of this coupling is evaluated. Early simplified, truncated FFs introduced to allow simulations of macromolecular systems are reviewed and their subsequent improvement assessed. We examine in some depth: the basis of the reformulation of the H-bond to its current description; the early introduction of QM in FF development methodology to calculate partial charges and rotational barriers; the powerful and abundant information provided by crystal structure and energetic observables to derive and test all aspects of a FF including both nonbond and intramolecular functional forms; the combined use of QM, along with crystallography and lattice energy calculations to derive rotational barriers about ? and ; the development and results of methodologies to derive QM FFs by sampling the QM energy surface, either by calculating energies at hundreds of configurations, or by describing the energy surface by energies, first and second derivatives sampled over the surface; and the use of the latter to probe the validity of the representations of the physics, reveal flaws and assess improved functional forms. Research demonstrating significant effects of the flaws in the use of the improper torsion angle to represent out of plane deformations, and the standard Lorentz-Berthelot combining rules for nonbonded interactions, and the more accurate descriptions presented are also reviewed. Finally, we discuss the thorough studies involved in deriving the 2nd generation all-atom versions of the CHARMm, AMBER and OPLS FFs, and how the extensive set of observables used in these studies allowed, in the spirit of Lifson, a characterization of both the abilities, but more importantly the deficiencies in the diagonal 12-6-1 FFs used. The significant contribution made by the extensive set of observables compiled in these papers as a basis to test improved forms is noted. In the following paper, we discuss the progress in improving the FFs and representations of the physics that have been investigated in the years following the research described above.