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A central question is how the conformational changes of proteins affect theirfunction and the inhibition of this function by drug molecules. Many enzymeschange from an open to a closed conformation upon binding of substrate orinhibitor molecules. These conformational changes have been suggested to followan induced-fit mechanism in which the molecules first bind in the openconformation in those cases where binding in the closed conformation appears tobe sterically obstructed such as for the HIV-1 protease. In this article, wepresent a general model for the catalysis and inhibition of enzymes withinduced-fit binding mechanism. We derive general expressions that specify howthe overall catalytic rate of the enzymes depends on the rates for binding, forthe conformational changes, and for the chemical reaction. Based on theseexpressions, we analyze the effect of mutations that mainly shift theconformational equilibrium on catalysis and inhibition. If the overallcatalytic rate is limited by product unbinding, we find that mutations thatdestabilize the closed conformation relative to the open conformation increasethe catalytic rate in the presence of inhibitors by a factor exp(ddG/RT) whereddG is the mutation-induced shift of the free-energy difference between theconformations. This increase in the catalytic rate due to changes in theconformational equilibrium is independent of the inhibitor molecule and, thus,may help to understand how non-active-site mutations can contribute to themulti-drug-resistance that has been observed for the HIV-1 protease. Acomparison to experimental data for the non-active-site mutation L90M of theHIV-1 protease indicates that the mutation slightly destabilizes the closedconformation of the enzyme.

biochimica et biophysica acta (bba) - proteins and proteomics

How conformational changes can affect catalysis, inhibition and drug  resistance of enzymes with induced-fit binding mechanism such as the HIV-1  protease