Polarizable Atomic Multipole Force Field for Biomacromolecules

生物大分子的可极化原子多极力场

• 批准号: 0344670
• 负责人: Jay Ponder
• 金额: --
• 依托单位: Washington University School of Medicine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0344670&HistoricalAwards=false
• 关键词: Polarizable; Atomic; Multipole; Force; Field

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.

该项目的目标是由分子生物物理学计划在分子和细胞生物科学划分中共同资助的，以及化学划分的理论和计算化学计划，是为了在蛋白质和蛋白质和料中的计算分析中使用一组一般势能函数，以验证一组一般的一般势能功能。这项工作是形式主义的变形虫（原子多极优化生物极化应用）的延伸。力场方法的所有应用都严重取决于潜在的经验能函数的准确性。对于生物分子，精确治疗静电，极化和环境影响是主要问题。传统的能量功能仅在平均均值场上具有环境效果。该项目提出了一种新的基于组的方案，该方案为分子间和分子内极化提供了一个一致的模型。该方法是第一个使用有效且易于区分的模型可靠地计算出柔性分子的分子极化性，静电电位和构象能的方法。主要目的是产生下一代能量模型，该模型通常在估计配体与蛋白质分子的热力学的估计中通常提供0.5 kcal/mol或更好的“化学准确性”。变形虫对极化原子多物种的使用导致对潜在的永久静电和对分子环境的响应的更灵活，更准确的描述。还以其他势能项进行了改进，包括有限的排斥分散相互作用的各向异性以及在选定的相邻扭转角之间使用耦合能的使用。 Amoeba力场为溶剂化的丙氨酸二肽提供了自由能，与量子机械结果非常吻合。新模型还能够将离子溶剂化的绝对自由能预测到化学精度内。这些一致且高度准确的绝对单离子值表明数十年的实验离子水合能可能需要重新解释。偏振还被认为在通过膜蛋白通道，离子迁移率和DNA结构凹槽中的浓度以及蛋白质二级结构和稳定性中发挥关键作用。经验潜在功能是一系列原子水平分子建模技术的基石。它们源自化学物理学的简单，经典的原理，并代表基于计算机的“球形”分子模型的类似物。因此，“分子力学”软件可以看到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到商业应用的设置。在华盛顿大学的研究和教学环境中，正在测试用于修补匠的新型Force Field Explorer（FFE）图形前端。最近，该大学组织了一个跨部门计算生物学中心（CCB），该中心将为整个校园提供分子和生物物理建模教学和研究的焦点。 Tinker和FFE将在新课程的“建模生物分子系统”中发挥关键作用，该课程是由CCB教师教授的团队。与课程相关的教学材料和建议的项目将通过互联网提供。 Tinker软件包将作为下一代部队现场努力的开发平台。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，并且在过去两年中发表的200多个被指导的科学论文中引用了该软件。与当前的情况一样，此项目下开发的修补源源代码和所有力场参数集将向任何感兴趣的各方免费使用。模块化的代码和参数的现成可用性也将使变形虫势能模型合并到其他，甚至更广泛使用的分子建模套件中。