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

该项目由分子和细胞生物科学部的分子生物物理学和化学部的理论和计算化学项目共同资助，目的是扩展目前用于生物分子系统建模的理论和计算方法，并开发和测试协议，这些协议将在估计自由能时提供更高的准确性和可靠性，同时保持计算可处理性。分子识别现象涉及配体与具有高亲和力和特异性的大分子的结合，在生物学中起着关键作用，是计算生物物理学中的一个核心问题。原则上，基于原子模型的分子动力学（MD）模拟自由能摄动（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。实验计算表明，在重要的生物系统中，MD/FEP比简单的评分方案更可靠地计算相对结合亲和力，并且可以很自然地处理动态灵活性的影响。然而，尽管模拟方法有了显著的发展，但对被显式溶剂分子包围的大分子组装体进行MD/FEP计算通常仍然是禁止的。因此，有必要寻求在保持MD/FEP计算精度的同时降低计算成本的方法。尽管人们对产生分子识别的基本微观相互作用的理解相对较好，但设计计算方案来精确计算结合自由能仍然是非常具有挑战性的。本研究的目的是提高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。教育和培训高素质人才是这一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来实施和测试。为了进一步扩大这项工作的影响，PI与CCNY化学系的Themis Lazaridis和Marilyn Gunner合作，监督CCNY（位于哈林区的一所拥有广泛种族群体的大学）本科生的研究项目。PI的实验室参与了三机构威尔-康奈尔-洛克菲勒-斯隆-凯特林通往实验室的通道计划，该计划旨在培养未被充分代表的少数民族学生成为成功的医学博士申请者。

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.