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

该项目的目标，共同资助的分子生物物理学在分子和细胞生物科学司和理论和计算化学计划在化学司，是扩大目前的理论和计算方法中使用的生物分子系统的建模和开发和测试协议，将提供更高的准确性和可靠性估计自由能，同时保持计算易处理。 涉及配体与高亲和力和特异性的大分子缔合的分子识别现象在生物学中起着关键作用，并且是计算生物物理学中的核心重要性问题。原则上，基于原子模型的分子动力学（MD）模拟自由能微扰（FEP）方法可以说是解决这些问题的最强大和最有前途的方法。测试计算表明，MD/FEP是更可靠的比简单的评分计划，以计算在重要的生物系统中的相对结合亲和力，它可以自然地处理动态灵活性的影响。然而，尽管在模拟方法的突出发展，进行MD/FEP计算的大分子组件所包围的明确的溶剂分子往往仍然令人望而却步。因此，有必要寻求降低MD/FEP计算的计算成本同时保持其准确性的方法。虽然引起分子识别的基本微观相互作用相对较好地理解，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。本研究的目标是推进用于估计生物系统中自由能的理论和计算方法的基础知识。高素质人员的教育和培训是该项目的一个内在组成部分。创新的理论发展将被实施，主要由研究生和博士后研究员实施和测试。为了进一步扩大这项工作的影响，PI已经与CCNY化学系的Themis Lazarlett和Marilyn Gunner合作，监督CCNY（一所位于哈莱姆的种族多样性大学）本科生的研究项目。 PI的实验室参加了Weill Cornell - Rockefeller - Sloan-Kettering三机构实验室门户计划，该计划培训代表性不足的少数民族学生成为成功的MD-PhD申请者。

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.