The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts
Publication information:
Spichty M, Taly A, Hagn F, Kessler H, Barluenga S, Winssinger N, Karplus M. The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts. Biophys. Chem. 2009;143(3):111–123.
Abstract
We det. the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and exptl. measurements. We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90. Docking poses are then evaluated by the use of binding free energy estns. with the linear interaction energy method. Comparison of QM/MM-calcd. NMR chem. shifts with exptl. shift data for a selective subset of backbone 15N provides an addnl. evaluation criteria. As a final test we check the binding modes against available structure-activity-relationships. We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex.