ABSTRACT

Adipocyte fatty-acid binding protein (A-FABP) plays a central role in many aspects of metabolic diseases. It is an important target in drug design for treatment of FABP-related diseases. In this study, molecular dynamics (MD) simulations followed by calculations of molecular mechanics generalized Born surface area (MM-GBSA) and principal components analysis (PCA) were implemented to decipher molecular mechanism correlating with binding of inhibitors 57Q, 57P and L96 to A-FABP. The results show that van der Waals interactions are the leading factors to control associations of 57Q, 57P, and L96 with A-FABP, which reveals an energetic basis for designing of clinically available inhibitors towards A-FABP. The information from PCA and cross-correlation analysis rationally unveils that inhibitor bindings affect conformational changes of A-FABP and change relative movements between residues. Decomposition of binding affinity into contributions of individual residues not only detects hot spots of inhibitor/A-FABP binding but also shows that polar interactions of the positively charged residue Arg126 with three inhibitors provide a significant contribution for stabilization of the inhibitor/A-FABP bindings. Furthermore, the binding strength of L96 to residues Ser55, Phe57 and Lys58 are stronger than that of inhibitors 57Q and 57P to these residues.

摘要

脂肪细胞脂肪酸结合蛋白（A-FABP）在代谢疾病的许多方面起着核心作用。它是用于治疗FABP相关疾病的药物设计的重要目标。在这项研究中，分子动力学（MD）模拟，接着进行分子力学广义玻恩表面积（MM-GBSA）和主成分分析（PCA）的计算，以破译与抑制剂57Q，57P和L96与A结合相关的分子机理-FABP。结果表明，范德华相互作用是控制57Q，57P和L96与A-FABP缔合的主要因素，这为设计临床可用的针对A-FABP的抑制剂提供了有力的基础。来自PCA和互相关分析的信息合理地揭示了抑制剂的结合会影响A-FABP的构象变化并改变残基之间的相对运动。结合亲和力分解成单个残基的贡献不仅检测抑制剂/ A-FABP结合的热点，而且还显示带正电荷的残基Arg126与三种抑制剂的极性相互作用为稳定抑制剂/ A-FABP结合提供了重要贡献。此外，L96与残基Ser55，Phe57和Lys58的结合强度比抑制剂57Q和57P对这些残基的结合强度更强。结合亲和力分解成单个残基的贡献不仅检测抑制剂/ A-FABP结合的热点，而且还显示带正电荷的残基Arg126与三种抑制剂的极性相互作用为稳定抑制剂/ A-FABP结合提供了重要贡献。此外，L96与残基Ser55，Phe57和Lys58的结合强度比抑制剂57Q和57P对这些残基的结合强度更强。结合亲和力分解成单个残基的贡献不仅检测抑制剂/ A-FABP结合的热点，而且还显示带正电荷的残基Arg126与三种抑制剂的极性相互作用为稳定抑制剂/ A-FABP结合提供了重要贡献。此外，L96与残基Ser55，Phe57和Lys58的结合强度比抑制剂57Q和57P对这些残基的结合强度更强。