Protein Polarization Is Critical to Stabilizing AF-2 and Helix-2′ Domains in Ligand Binding to PPAR-γ

• Published in: Journal of the American Chemical Society 2008-12, Vol.130 (50), p.17129-17133
• Main Authors: Ji, C. G, Zhang, J. Z. H
• Format: Article
• Language: English
• Subjects: Computer Simulation; Crystallography, X-Ray; Hydrogen Bonding; Ligands; Models, Molecular; PPAR gamma - chemistry; PPAR gamma - metabolism; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Time Factors
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja807374x

The peroxisome proliferator-activated receptor (PPAR-γ) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis. This paper presents a detailed dynamics study of PPAR-γ 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-γ and a helix structure (helix-2′). Specifically when nonpolarized force field is used, a critical H-bond in PPAR-γ 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-γ 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-γ.