The importance of hydrophobic residues to the binding of methotrexate in the active site of dihydrofolate reductase (EC 18.104.22.168) 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 language||English (US)|
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 1988|
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