Molecular Modelling Lab, Food and Drug Department, University of Parma, Parco Area delle Scienze, 17/A, 43121 Parma, Italy.
Molecules. 2024 May 10;29(10):2234. doi: 10.3390/molecules29102234.
Molecular Dynamics (MD) is a computational technique widely used to evaluate a molecular system's thermodynamic properties and conformational behavior over time. In particular, the energy analysis of a protein conformation ensemble produced though MD simulations plays a crucial role in explaining the relationship between protein dynamics and its mechanism of action. In this research work, the HINT (Hydropathic INTeractions) LogP-based scoring function was first used to handle MD trajectories and investigate the molecular basis behind the intricate PPARγ mechanism of activation. The Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an emblematic example of a highly flexible protein due to the extended ω-loop delimiting the active site, and it is responsible for the receptor's ability to bind chemically different compounds. In this work, we focused on the PPARγ complex with Rosiglitazone, a common anti-diabetic compound and analyzed the molecular basis of the flexible ω-loop stabilization effect produced by the Oleic Acid co-binding. The HINT-based analysis of the produced MD trajectories allowed us to account for all of the energetic contributions involved in interconverting between conformational states and describe the intramolecular interactions between the flexible ω-loop and the helix H3 triggered by the allosteric binding mechanism.
分子动力学（MD）是一种广泛用于评估分子系统随时间的热力学性质和构象行为的计算技术。特别是，通过 MD 模拟产生的蛋白质构象集合的能量分析在解释蛋白质动力学与其作用机制之间的关系方面起着至关重要的作用。在这项研究工作中，首先使用基于 HINT（疏水性相互作用）LogP 的评分函数来处理 MD 轨迹，并研究激活复杂的 PPARγ 机制背后的分子基础。过氧化物酶体增殖物激活受体 γ（PPARγ）是高度灵活蛋白质的典型代表，因为扩展的 ω-环限制了活性部位，它负责受体结合化学上不同化合物的能力。在这项工作中，我们专注于与罗格列酮结合的 PPARγ 复合物，罗格列酮是一种常见的抗糖尿病化合物，并分析了油酸共结合产生的柔性 ω-环稳定化效应的分子基础。所产生的 MD 轨迹的基于 HINT 的分析允许我们解释在构象状态之间转换涉及的所有能量贡献，并描述由变构结合机制触发的柔性 ω-环和螺旋 H3 之间的分子内相互作用。
