Molecular mechanisms of inhibitor bindings to A-FABP deciphered by using molecular dynamics simulations and calculations of MM-GBSA

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.

KEYWORDS:

• A-FABP
• molecular dynamics simulations
• MM-GBSA
• principal components analysis
• cross-correlation analysis

Acknowledgements

This work is supported by the National Science Foundation of China (No.12004216), Science Foundation of Shandong Jiaotong University (No.Z201810) and (No.BS20192002040). The authors sincerely thank Prof. Jianzhong Chen (School of Science, Shandong Jiaotong University, Jinan 250357, China) for useful discussions and invaluable comments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work is supported by the National Science Foundation of China (No. 12004216), Science Foundation of Shandong Jiaotong University (No.Z201810) and (No.BS20192002040)