Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 41, Issue 17, Pages 1606-1615Publisher
WILEY
DOI: 10.1002/jcc.26203
Keywords
dynamic docking; enhanced conformational sampling; free energy landscape; heat-shock protein 90; multicanonical Molecular Dynamics
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Multicanonical molecular dynamics based dynamic docking was used to exhaustively search the configurational space of an inhibitor binding to the N-terminal domain of heat-shock protein 90 (Hsp90). The obtained structures at 300K cover a wide structural ensemble, with the top two clusters ranked by their free energy coinciding with the native binding site. The representative structure of the most stable cluster reproduced the experimental binding configuration, but an interesting conformational change in Hsp90 could be observed. The combined effects of solvation and ligand binding shift the equilibrium from a preferred loop-in conformation in the unbound state to an alpha -helical one in the bound state for the flexible lid region of Hsp90. Thus, our dynamic docking method is effective at predicting the native binding site while exhaustively sampling a wide configurational space, modulating the protein structure upon binding.
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