Fossat Martin J, Zeng Xiangze, Pappu Rohit V
Department of Biomedical Engineering and Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, Missouri 63130, United States.
J Phys Chem B. 2021 Apr 29;125(16):4148-4161. doi: 10.1021/acs.jpcb.1c01073. Epub 2021 Apr 20.
Free energies of hydration are of fundamental interest for modeling and understanding conformational and phase equilibria of macromolecular solutes in aqueous phases. Of particular relevance to systems such as intrinsically disordered proteins are the free energies of hydration and hydration structures of model compounds that mimic charged side chains of Arg, Lys, Asp, and Glu. Here, we deploy a Thermodynamic Cycle-based Proton Dissociation (TCPD) approach in conjunction with data from direct measurements to obtain estimates for the free energies of hydration for model compounds that mimic the side chains of Arg, Lys, Asp, and Glu. Irrespective of the choice made for the hydration free energy of the proton, the TCPD approach reveals clear trends regarding the free energies of hydration for Arg, Lys, Asp, and Glu. These trends include asymmetries between the hydration free energies of acidic (Asp and Glu) and basic (Arg and Lys) residues. Further, the TCPD analysis, which relies on a combination of experimental data, shows that the free energy of hydration of Arg is less favorable than that of Lys. We sought a physical explanation for the TCPD-derived trends in free energies of hydration. To this end, we performed temperature-dependent calculations of free energies of hydration and analyzed hydration structures from simulations that use the polarizable Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field and water model. At 298 K, the AMOEBA model generates estimates of free energies of hydration that are consistent with TCPD values with a free energy of hydration for the proton of ca. -259 kcal/mol. Analysis of temperature-dependent simulations leads to a structural explanation for the observed differences in free energies of hydration of ionizable residues and reveals that the heat capacity of hydration is positive for Arg and Lys and negative for Asp and Glu.
水合自由能对于模拟和理解水相中大分子溶质的构象和相平衡具有根本重要性。对于诸如内在无序蛋白质等系统而言，特别相关的是模拟精氨酸（Arg）、赖氨酸（Lys）、天冬氨酸（Asp）和谷氨酸（Glu）带电侧链的模型化合物的水合自由能和水合结构。在此，我们采用基于热力学循环的质子解离（TCPD）方法，并结合直接测量数据，以获得模拟Arg、Lys、Asp和Glu侧链的模型化合物的水合自由能估计值。无论对质子的水合自由能做出何种选择，TCPD方法都揭示了关于Arg、Lys、Asp和Glu水合自由能的明显趋势。这些趋势包括酸性（Asp和Glu）和碱性（Arg和Lys）残基水合自由能之间的不对称性。此外，依赖于实验数据组合的TCPD分析表明，Arg的水合自由能比Lys的更不利。我们寻求对TCPD推导的水合自由能趋势的物理解释。为此，我们进行了水合自由能的温度依赖性计算，并分析了使用用于生物分子应用的可极化原子多极优化能量学（AMOEBA）力场和水模型的模拟中的水合结构。在298K时，AMOEBA模型生成的水合自由能估计值与TCPD值一致，质子的水合自由能约为-259千卡/摩尔。对温度依赖性模拟的分析为可电离残基水合自由能的观察到的差异提供了结构解释，并揭示了Arg和Lys的水合热容量为正，而Asp和Glu的为负。
