Changes in the electron density of the cofactor NADPH on binding to E. coli dihydrofolate reductase

✍ Scribed by Jürgen Bajorath; Zhenqin Li; George Fitzgerald; David H. Kitson; Martin Farnum; Richard M. Fine; Joseph Kraut; Dr. Arnold T. Hagler

• Book ID: 105358602
• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: English
• Weight: 941 KB
• Volume: 11
• Category: Article
• ISSN: 0887-3585
• DOI: 10.1002/prot.340110405

✦ Synopsis

Abstract

Quantum‐mechanical electron density calculations reveal that a significant polarization is induced in the cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate) on binding to the enzyme dihydrofolate reductase. The calculations indicate that electron density corresponding to ∼0.7 electron charges is shifted within the molecule, extending over more than 20Å. Further calculations on proposed enzyme mutants show that the polarization of NADPH on binding to DHFR is, in large part, induced by a motif of three positively charged residues. This motif was also identified to be directly responsible for the positive electrostatic potential surrounding the cofactor binding site in the enzyme. The possibility of this long‐range polarization of NADPH was originally proposed based on a previous study of ligand binding to DHFR where a conserved structural motif of three positively charged residues was found to play a major role in polarizing the substrate folate over its entire length of 18 Å.