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A Free-Energy Perturbation Study of the Binding of Methotrexate to Mutants of Dihydrofolate Reductase

U. C. Singh and S. J. Benkovic
Proceedings of the National Academy of Sciences of the United States of America
Vol. 85, No. 24 (Dec. 15, 1988), pp. 9519-9523
Stable URL: http://www.jstor.org/stable/32666
Page Count: 5
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
A Free-Energy Perturbation Study of the Binding of Methotrexate to Mutants of Dihydrofolate Reductase
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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.

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