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计划共同资助，其目标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，在保持计算简单性的同时，在估计自由能方面提供更高的准确性和可靠性。分子识别现象涉及配体与具有高亲和力和高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核心问题。从理论上讲，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有效和最有前途的方法。测试计算表明，在计算重要生物系统的相对结合亲和力时，MD/FEP比更简单的计分方法可靠得多，而且它自然可以处理动态灵活性的影响。然而，尽管在模拟方法方面有了很大的发展，但对被显性溶剂分子包围的大分子组装进行MD/FEP计算往往仍然是令人望而却步的。因此，有必要设法在保证计算精度的同时降低MD/FEP计算的计算量。尽管引起分子识别的基本微观相互作用相对较好地被理解，但是设计计算方案来准确地计算结合自由能仍然是非常具有挑战性的。这项研究的目的是提高用于估计生物系统自由能的理论和计算方法的基础知识。高素质人才的教育和培训是这一项目的内在组成部分。创新的理论发展将被实施，并由研究生和博士后研究员初步实施和测试。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开展了合作，以监督CCNY(位于哈莱姆区的一所大学)本科生的研究项目。国际学生联合会的实验室参与了威尔康奈尔-洛克菲勒-斯隆-凯特琳三所大学的实验室之门项目，该项目培训未被充分代表的少数族裔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.