Department of Chemistry, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, South Korea.
Department of Chemistry and Institute of Functional Materials, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, South Korea.
J Chem Theory Comput. 2021 Jan 12;17(1):515-524. doi: 10.1021/acs.jctc.0c01046. Epub 2020 Dec 8.
Fully atomistic replica exchange molecular dynamics simulations are performed to compute the stability curve of a small globular protein as accurately as possible. To investigate the individual roles of the protein and water parts, we compute the conformational entropy change of this protein directly from the simulation ensembles. This entropy calculation enables complete separations of the unfolding changes of enthalpy and the entropy into their own protein and hydration components. From this decomposition, we are able to determine the main thermodynamic factors governing the cold and heat unfolding events: the cold and heat unfolding events are largely driven by the hydration enthalpy gain and the protein conformational entropy gain, respectively. This computational study discloses several temperature-dependent unfolding thermodynamic behaviors of the protein and water compartments and establishes their unique relationship. Upon unfolding, the changes of enthalpy and entropy in the protein part are all positive convex functions of temperature, whereas the equivalent changes in the water part are all negative concave functions of temperature. Hence, these two mutually opposing effects from the protein and water parts dictate the thermodynamics of unfolding. Furthermore, consistent with the temperature-dependent behaviors of the protein part, the changes of the solvent-accessible surface area and the radius of gyration of the protein upon unfolding are also convex functions of temperature. Hence, all these new temperature dependences, combined together, pave the way to unveiling the thermodynamic and structural features of protein denaturation events at various temperature conditions.
我们进行了全原子 replica 交换分子动力学模拟，以尽可能准确地计算小分子球状蛋白的稳定性曲线。为了研究蛋白和水的各自作用，我们直接从模拟体系中计算该蛋白的构象熵变化。这种熵的计算使得焓和熵的展开变化能够完全分离为各自的蛋白和水合部分。通过这种分解，我们能够确定控制冷和热展开事件的主要热力学因素：冷和热展开事件主要分别由水合焓增加和蛋白构象熵增加驱动。这项计算研究揭示了蛋白和水相的几个与温度相关的展开热力学行为，并建立了它们独特的关系。在展开过程中，蛋白部分的焓和熵变化都是温度的正凸函数，而水相的等效变化都是温度的负凹函数。因此，蛋白和水相的这两个相互对立的效应决定了展开的热力学。此外，与蛋白部分的温度依赖性一致，蛋白在展开时的溶剂可及表面积和回转半径的变化也是温度的凸函数。因此，所有这些新的温度依赖性结合在一起，为揭示在各种温度条件下蛋白变性事件的热力学和结构特征铺平了道路。
