Ji C G, Zhang J Z H
Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
J Am Chem Soc. 2008 Dec 17;130(50):17129-33. doi: 10.1021/ja807374x.
The peroxisome proliferator-activated receptor (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis. This paper presents a detailed dynamics study of PPAR-gamma and its binding to the agonist rosiglitazone using both polarized and unpolarized force fields. The numerical result revealed the critical role of protein polarization in stabilizing the activation function-2 (AF-2) in ligand binding to PPAR-gamma and a helix structure (helix-2'). Specifically when nonpolarized force field is used, a critical H-bond in PPAR-gamma binding is broken, which caused AF-2 to adopt random structures. In addition, helix-2' is partially denatured during the MD simulation, due to the breaking of a backbone hydrogen bond. In contrast, when polarized force field is employed in MD simulation, the PPAR-gamma ligand binding structure is stabilized and the local structure of helix-2' remains folded, both being in excellent agreement with experimental observations. The current result demonstrates the importance of electronic polarization of protein in stabilizing hydrogen bonding, which is critical to preserving the native structure of local helices and protein-ligand binding in PPAR-gamma.
过氧化物酶体增殖物激活受体（PPAR-γ）是一种依赖配体的转录因子，在脂肪细胞分化和葡萄糖稳态中起重要作用。本文使用极化和非极化力场对PPAR-γ及其与激动剂罗格列酮的结合进行了详细的动力学研究。数值结果揭示了蛋白质极化在稳定配体与PPAR-γ结合中的激活功能-2（AF-2）和螺旋结构（螺旋-2'）方面的关键作用。具体而言，当使用非极化力场时，PPAR-γ结合中的一个关键氢键断裂，导致AF-2采用随机结构。此外，在分子动力学模拟过程中，由于主链氢键的断裂，螺旋-2'部分变性。相比之下，当在分子动力学模拟中采用极化力场时，PPAR-γ配体结合结构得以稳定，螺旋-2'的局部结构保持折叠状态，两者均与实验观察结果高度吻合。当前结果证明了蛋白质电子极化在稳定氢键方面的重要性，这对于维持PPAR-γ中局部螺旋的天然结构和蛋白质-配体结合至关重要。
