Calculation of relative binding affinities of fructose 1,6-bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

✍ Scribed by Ravichandra Mutyala; R. N. Reddy; M. Sumakanth; P. Reddanna; M. Rami Reddy

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 185 KB
• Volume: 28
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.20617

✦ Synopsis

Abstract

The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6‐bisphosphatase (FBPase), a target enzyme for type‐II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: ^113^Tyr → ^113^Phe, ^31^Thr → ^31^Ala, ^31^Thr → ^31^Ser, ^177^Met → ^177^Ala, and ^30^Leu → ^30^Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: ^113^Tyr and ^31^Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007