Free Energies in Biomolecular Systems: Theoretical Development and Application of Computational Approaches

生物分子系统中的自由能：计算方法的理论发展和应用

• 批准号: 0415784
• 负责人: Benoit Roux
• 金额: $ 64.31万
• 依托单位: Joan and Sanford I. Weill Medical College of Cornell University
• 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: 2004-09-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0415784&HistoricalAwards=false
• 关键词: Free; Energies; Biomolecular; Systems; Theoretical

The objective of this project, jointly funded by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to extend current theoretical and computational approaches used in the modeling of biomolecular systems and to develop and test protocols that will provide increased accuracy and reliability in estimating free energies while remaining computationally tractable. Molecular recognition phenomena involving the association of ligands to macromolecules with high affinity and specificity play a key role in biology and is a problem of central importance in computational biophysics. In principle, molecular dynamics (MD) simulations free energy perturbation (FEP) methods based on atomic models are arguably the most powerful and promising approaches to address such questions. Test calculations have shown that MD/FEP is much more reliable than simpler scoring schemes to compute relative binding affinities in important biological systems and that it can naturally handle the influence of dynamic flexibility. However, despite the outstanding developments in simulation methodologies, carrying out MD/FEP calculations of large macromolecular assemblies surrounded by explicit solvent molecules often remain prohibitive. For this reason, it is necessary to seek ways to decrease the computational cost of MD/FEP calculations while keeping them accurate. Although the fundamental microscopic interactions giving rise to molecular recognition are relatively well-understood, designing computational schemes to accurately calculate binding free energies remains very challenging. The goal of this research is to advance the fundamental knowledge in the theoretical and computational methodologies used to estimate free energies in biological systems. The education and training of highly qualified personnel is an intrinsic component of this project. The innovative theoretical developments will be implemented and primarily implemented and tested by graduate students and postdoctoral fellows. To further broaden the impact of this work, the PI has developed collaboration with Themis Lazaridis and Marilyn Gunner from the Chemistry Department at CCNY, to supervise research projects by undergraduate students from CCNY (a university with a wide diversity of ethnic groups located in Harlem). The PI's laboratory participates in the Tri-Institutional Weill Cornell - Rockefeller - Sloan-Kettering Gateways to the Laboratory Program, which trains underrepresented minority students to become successful MD-PhD applicants.

该项目的目的是由分子生物物理学在分子和细胞生物科学的划分中共同资助的，以及化学部门的理论和计算化学计划，是为了扩展当前的理论和计算方法，用于建模生物分子系统，并在估算估计的计算中提供了增强的准确性和可靠性。 分子识别现象涉及配体与高亲和力和特异性的大分子的关联在生物学中起关键作用，并且在计算生物物理学中是核心重要性的问题。原则上，基于原子模型的分子动力学（MD）模拟自由能扰动（FEP）方法可以说是解决此类问题的最强大和最有希望的方法。测试计算表明，MD/FEP比更简单的评分方案要可靠得多，以计算重要的生物系统中的相对结合亲和力，并且可以自然处理动态灵活性的影响。然而，尽管模拟方法方面有出色的发展，但对被显式溶剂分子包围的大型大分子组件进行MD/FEP计算通常仍然令人望而却步。因此，有必要寻求方法来降低MD/FEP计算的计算成本，同时保持准确性。尽管引起分子识别的基本微观相互作用是相对良好的理解，但设计计算方案以准确计算结合自由能仍然非常具有挑战性。这项研究的目的是推进用于估计生物系统自由能的理论和计算方法中的基本知识。高素质人员的教育和培训是该项目的内在组成部分。创新的理论发展将由研究生和博士后研究员实施，主要实施和测试。为了进一步扩大这项工作的影响，PI已与CCNY化学系的Themis Lazaridis和Marilyn Gunner建立了合作，以通过CCNY的本科生（一所在Harlem拥有​​广泛多样性的族裔群体）的本科生监督研究项目。 PI的实验室参加了三机构的Weill Cornell-Rockefeller-Sloan-Kettering Gateways通往实验室计划，该计划培训了代表性不足的少数民族学生，成为成功的MD-PHD申请人。