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The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts.
Biophys Chem, 143(3):111-23.
We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We samplethe macrocyclic scaffold of the unbound ligand by parallel tempering simulationsand dock the most populated conformations to yeast HSP90. Docking poses are thenevaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of backbone (15)N provides an additional evaluation criteria. As a final test we check the binding modes against available structure-activity-relationships. We find that the most likelybinding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex.
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