A free-energy perturbation study of the binding of methotrexate to mutants of dihydrofolate reductase

U. C. Singh, S. J. Benkovic

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Abstract

The importance of hydrophobic residues to the binding of methotrexate in the active site of dihydrofolate reductase (EC 1.5.1.3) was examined by a free-energy perturbation method. The replacement of a strictly conserved residue, Phe-31, by tyrosine or valine costs 1.8 and 5.1 kcal/mol, respectively, to the binding of the drug (1 cal = 4.184 J). In the case of the Phe31 → Tyr mutation, the loss of the binding energy is due to the desolvation of the phenolic group; in the case of Phe31 → Val mutation, it is mainly due to the loss of the interaction with the drug. The replacement of Leu-54 by glycine decreases the binding energy by 4.0 kcal/mol. A calculation on the mutation of Phe-31 to serine shows that the alteration could reduce the binding energy of methotrexate by 9.7 kcal/mol. The calculations clearly show that the hydrophobic interactions are as important as the hydrophilic ones in the binding of methotrexate.

Original languageEnglish (US)
Pages (from-to)9519-9523
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume85
Issue number24
DOIs
StatePublished - 1988

All Science Journal Classification (ASJC) codes

  • General

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