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

生物分子系统中的自由能：计算方法的开发和应用

• 批准号: 0110847
• 负责人: Benoit Roux
• 金额: $ 33万
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0110847&HistoricalAwards=false
• 关键词: Free; Energies; Biomolecular; Systems; Development

By and large, biological processes involving ligand binding specificity, protein-protein association, protein-membrane association, protonation and unprotonation of ionizable groups, and macromolecular conformational changes, are given thermodynamically by a reversible work function, the free energy, or more generally by its configuration-dependent equivalent. A quantitative determination of free energies is, therefore, a problem of central importance in theoretical biophysics. Computational approaches at different levels of complexity and sophistication can be used to try and address this problem. Those range from (relatively expensive) molecular dynamics free energy simulations (MD/FES) based on all-atom models in which the solvent is treated explicitly to (relative inexpensive) Poisson-Boltzmann (PB) continuum electrostatic models in which the influence of the solvent is incorporated implicitly. The goal of this research is to refine and extend current computational approaches used in the modeling of biomolecular systems. More particularly, protocols that will provide increased accuracy and reliability in estimating free energies while remaining computationally tractable will be developed and tested. Progress in these computational methodologies is expected to have a great impact on the rational design of drugs and biomolecules.

总体而言，涉及配体结合特异性，蛋白质 - 蛋白质缔合，蛋白质 - 膜缔合，蛋白质 - 蛋白质缔合，可离子化基团的质子化和脱位以及大分子构象变化的生物学过程是由可逆的工作功能，自由能，自由能，或更普遍地通过其构型依赖性等价的。 因此，对自由能的定量确定是理论生物物理学中至关重要的问题。 可以使用不同级别的复杂性和复杂性的计算方法来尝试解决此问题。 这些范围从基于全原子模型的（相对昂贵的）分子动力学自由能模拟（MD/FES），其中将溶剂明确处理为（相对廉价的）Poisson-Boltzmann（PB）持续静电模型，其中隐含溶剂的影响。 这项研究的目的是完善和扩展用于生物分子系统建模的当前计算方法。 尤其是，将开发和测试剩余的计算可行的同时估算自由能，同时估算自由能的准确性和可靠性。 这些计算方法中的进展有望对药物和生物分子的合理设计产生重大影响。