Thermodynamics of strongly allosteric inhibition: a model study of HIV-1 protease.
Protein inhibitors that shift the thermodynamic equilibrium towards a denatured state escape, in general, the straightforward framework of competitive or allosteric inhibitors. The equilibrium properties of peptides which compete with the folding, or more precisely destabilize the native state, of the human immunodeficiency virus (HIV)-1 protease monomer are studied within a structure-based model. The effect of peptides that disrupt the hydrophobic core of the protein can still be summarized in terms of an inhibition constant, which depends on the thermal stability of the protein. The state of the protein denatured by such a peptide is more structured than its intrinsic denatured state, but displays the same degree of compactness. Peptides that target less buried regions of the protein are less efficient and display a more complex thermodynamics that cannot be captured in a simple way.
Department of Physics, University of Milano, via Celoria 16, 20133 Milan, Italy.
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Kimura
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Broglia
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Tiana
D000494:Allosteric Regulation; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects; D008956:Models, Chemical; D011480:Protease Inhibitors / Q000494:pharmacology; D017510:Protein Folding; D055550:Protein Stability; D013816:Thermodynamics
D011480:Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1