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

总的来说，涉及配体结合特异性、蛋白质-蛋白质缔合、蛋白质-膜缔合、可电离基团的质子化和非质子化以及大分子构象变化的生物学过程由可逆功函数、自由能或更一般地由其构型依赖性等价物在化学上给出。 因此，自由能的定量测定是理论生物物理学中的一个重要问题。 可以使用不同复杂程度和复杂程度的计算方法来尝试解决这个问题。 这些范围从（相对昂贵的）分子动力学自由能模拟（MD/FES）的基础上的所有原子模型，其中的溶剂是显式处理（相对便宜）泊松-玻尔兹曼（PB）连续静电模型，其中的溶剂的影响是隐含的。 本研究的目标是改进和扩展目前用于生物分子系统建模的计算方法。 更具体地说，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的将开发和测试。 这些计算方法的进展预计将对药物和生物分子的合理设计产生重大影响。

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.