Electrostatic interaction-mediated conformational changes of adipocyte fatty acid binding protein probed by molecular...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Adipocyte fatty acid binding protein (A-FABP) is a key target for treating diabetes, obesity, and atherosclerosis.
• Understanding A-FABP's structural dynamics is vital for developing effective therapeutic inhibitors.

Purpose of the Study:

• To investigate the role of electrostatic interactions involving residues R78, R106, and R126 in A-FABP.
• To determine the impact of these interactions on the structural stability of A-FABP in complex with inhibitors ZGB, ZGC, and IBP.
• To provide theoretical guidance for designing novel A-FABP inhibitors.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze protein-ligand interactions.
• Principal component (PC) analysis was used to study conformational changes.
• Binding free energy calculations assessed the stability of inhibitor/A-FABP complexes.

Main Results:

• Mutation R126A significantly altered polar interactions between inhibitors and A-FABP, driving conformational changes.
• Changes in hydrogen bonding at residues R126, Y128, and K58 were identified as key regulators of A-FABP conformation.
• The R126A mutation caused substantial perturbations in A-FABP's structural stability.

Conclusions:

• Residue R126 plays a critical role in inhibitor binding to A-FABP.
• Targeting R126 interactions can modulate A-FABP structure and function.
• This study offers valuable insights for the rational design of potent A-FABP inhibitors.