Antihydrophobic Solvent Effects: An Experimental Probe for the Hydrophobic Contribution to Enzyme-Inhibitor Binding

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• 作者：Paul A. Bartlett ; Naeem Yusuff ; Alice C. Rico ; and Mika K. Lindvall
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：April 17, 2002
• 年：2002
• 卷：124
• 期：15
• 页码：3853 - 3857
• 全文大小：535K
• 年卷期：v.124,no.15(April 17, 2002)
• ISSN：1520-5126

文摘

The hydrophobic component to the binding affinities of one acyclic phosphinate (4) and threemacrocyclic phosphonamidate inhibitors (1-3) to the zinc peptidase thermolysin was probed by varyingthe solvent composition. Increasing the percentage of ethanol in the buffer solution over the range 0-9%increases the inhibition constants, K_i, by up to an order of magnitude. This approach represents anexperimental method for distinguishing solvation from conformational or other effects on protein-ligandbinding. The size of the "antihydrophobic effect" is correlated with the amount of hydrophobic surface areasequestered from solvent on association of the inhibitor and enzyme, although it is attenuated from thatcalculated from the surface tension of ethanol-water mixtures. The results are consistent with the Lum-Chandler-Weeks explanation for the size dependence of the hydrophobic effect.