Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases

0427922 - ÚOCHB 2015 RIV GB eng J - Journal Article
Kožíšek, Milan - Lepšík, Martin - Grantz Šašková, Klára - Brynda, Jiří - Konvalinka, Jan - Řezáčová, Pavlína
Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases.
FEBS Journal. Roč. 281, č. 7 (2014), s. 1834-1847. ISSN 1742-464X. E-ISSN 1742-4658
R&D Projects: GA ČR GAP207/11/1798
Grant - others:OPPC(XE) CZ.2.16/3.1.00/24016
Institutional support: RVO:61388963 ; RVO:68378050
Keywords : enthropic contribution * HIV protease inhibitors * isothermal titration calorimetry * resistance mutation * X-ray crystallography
Subject RIV: CE - Biochemistry
Impact factor: 4.001, year: 2014

We report enzymologic, thermodynamic and structural analyses of a series of six clinically derived mutant HIV proteases (PR) resistant to darunavir. As many as 20 mutations in the resistant PRs decreased the binding affinity of darunavir by up to 13000-fold, mostly because of a less favorable enthalpy of binding that was only partially compensated by the entropic contribution. X-ray structure analysis suggested that the drop in enthalpy of darunavir binding to resistantPR species was mostly the result of a decrease in the number of hydrogen bonds and a loosening of the fit between the inhibitor and the mutated enzymes. The favorable entropic contribution to darunavir binding to mutated PR variants correlated with a larger burial of the nonpolar solvent-accessible surface area upon inhibitor binding. We show that even very dramatic changes in the PR sequence leading to the loss of hydrogen bonds with the inhibitor could be partially compensated by the entropy contribution as a result of the burial of the larger nonpolar surface area of the mutated HIV PRs.
Permanent Link: http://hdl.handle.net/11104/0233503