Polarizable Atomic Multipole Force Field for Biomacromolecules

该项目的目标，由分子和细胞生物科学部的分子生物物理计划和化学部的理论和计算化学计划共同资助，是最终确定和验证一套改进的一般势能函数，“力场”，用于蛋白质和配体分子的计算分析。这项工作是AMOEBA（原子多极优化能量学的生物分子应用）形式主义的扩展。力场方法的所有应用都严格依赖于基本经验能量函数的准确性。对于生物分子，静电、极化和环境效应的精确处理是主要关注的问题。传统的能量函数仅在平均、平均场意义上包括环境效应。该项目提出了一种新的基于基团的方案，该方案产生了分子间和分子内极化的一致模型。这种方法是第一个可靠地计算分子的极化率，静电势和灵活的分子的构象能量与一个有效的和容易区分的模型适合冗长的分子动力学模拟或构象搜索协议。主要目的是产生下一代能量模型，该模型将在配体与蛋白质分子结合的热力学估计中常规地提供0.5千卡/摩尔或更好的“化学准确度”。AMOEBA使用可极化的原子多极导致对潜在的永久静电和对分子环境的响应的更灵活和准确的描述。在其他势能项中也进行了改进，包括排斥-色散相互作用的有限各向异性和所选相邻扭转角之间的耦合能的使用。AMOEBA力场提供了与量子力学结果非常一致的溶剂化丙氨酸二肽的自由能。新模型也能够预测绝对自由能的离子溶剂化的化学精度。这些一致和高度准确的绝对单离子值表明几十年前的实验离子水合能可能需要重新解释。极化也被认为在离子通过膜蛋白通道的转运、离子在DNA结构沟中的迁移率和浓度以及蛋白质二级结构和稳定性中起着关键作用。经验势函数是大量原子水平分子模拟技术的基石。它们源自简单的、经典的化学物理学原理，代表了基于计算机的物理“球杆”分子模型的模拟。因此，“分子力学”软件的使用范围从本科化学和生物化学课程到分子生物物理学的高级研究再到商业应用。TINKER的新力场探测器（FFE）图形前端正在华盛顿大学的研究和教学环境中进行测试。最近，该大学组织了一个跨部门的计算生物学中心（CCB），该中心将为分子和生物物理建模的教学和研究提供一个全校园的焦点。TINKER和FFE将在新课程“生物分子系统建模”中发挥关键作用，该课程由CCB教师团队授课。与课程有关的教学材料和建议的项目将通过因特网提供。TINKER包将作为下一代部队领域工作的开发平台。该软件目前在全球范围内被多达20，000名研究人员和实验室使用，并在过去两年中发表的200多篇经过评审的科学论文中被引用。与目前的情况一样，TINKER源代码和在该项目下开发的所有力场参数集将继续免费提供给任何感兴趣的各方。模块化的现成可用性，记录的代码和参数也将使AMOEBA势能模型纳入其他，甚至更广泛使用的分子建模套件。

The goal of this project, funded jointly by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to finalize and validate an improved set of general potential energy functions, a "force field", for use in computational analysis of proteins and ligand molecules. This work is an extension of the AMOEBA (Atomic Multipole Optimized Energetics for Biomoleuclar Applications) formalism. All applications of force field methodology are critically dependent on the accuracy of the underlying empirical energy functions. For biomolecules, accurate treatment of electrostatics, polarization and environmental effects is of major concern. Traditional energy functions include environmental effects in only an average, mean-field sense. This project proposes a new group-based scheme that yields a consistent model for both inter- and intramolecular polarization. This methodology is the first to reliably compute the molecular polarizability, electrostatic potential and conformational energetics of flexible molecules with an efficient and easily differentiable model suitable for lengthy molecular dynamics simulations or conformational search protocols. The major aim is to produce a next-generation energy model that will routinely provide "chemical accuracy" of 0.5 kcal/mol or better in the estimation of the thermodynamics of ligand binding to protein molecules. AMOEBA's use of polarizable atomic multipoles results in a much more flexible and accurate description of the underlying permanent electrostatics and response to the molecular environment. Improvements are also made in other potential energy terms, including limited anisotropy of repulsion-dispersion interactions and use of coupling energies between selected adjacent torsional angles. The AMOEBA force field provides free energies for the solvated alanine dipeptide in excellent agreement with quantum mechanical results. The new model is also capable of predicting absolute free energies of ion solvation to within chemical accuracy. These consistent and highly accurate absolute single ion values suggest decades-old experimental ion hydration energies may need reinterpretation. Polarization is also considered to play a key role in ion transport through membrane protein channels, ion mobility and concentration in DNA structural grooves, and protein secondary structure and stability.Empirical potential functions are the cornerstone of a vast array of atomic-level molecular modeling techniques. They derive from simple, classical principles of chemical physics, and represent the computer-based analog of physical "ball-and-stick" molecular models. As such, "molecular mechanics" software sees use in settings ranging from undergraduate chemistry and biochemistry courses to advanced research in molecular biophysics to commercial applications. The new Force Field Explorer (FFE) graphical front-end for TINKER is being tested in both research and teaching environments at Washington University. Recently, the University has organized an interdepartmental Center for Computational Biology (CCB), which will provide a campus-wide focal point for teaching and research in molecular and biophysical modeling. TINKER and FFE will play a key role in a new course, "Modeling Biomolecular Systems", which is team-taught by the CCB faculty. Course-related instructional materials and suggested projects will be made available via the Internet. The TINKER package will serve as the development platform for the next-generation force field efforts. The software is presently used worldwide by as many as 20,000 researchers and laboratories, and is cited in over 200 refereed scientific papers published within the past two years. As is currently the case, the TINKER source code and all force field parameter sets developed under this project will remain freely available to any interested parties. The ready availability of modular, documented code and parameters will also enable the incorporation of the AMOEBA potential energy model into other, even more widely used, molecular modeling suites.