Exhaustive search of the configurational space of heat‐shock protein 90 with its inhibitor by multicanonical molecular dynamics based dynamic docking

• Published in: Journal of computational chemistry 2020-06, Vol.41 (17), p.1606-1615
• Main Authors: Bekker, Gert‐Jan, Araki, Mitsugu, Oshima, Kanji, Okuno, Yasushi, Kamiya, Narutoshi
• Format: Article
• Language: English
• Subjects: Binding sites; dynamic docking; enhanced conformational sampling; Free energy; free energy landscape; Heat shock proteins; heat‐shock protein 90; Inhibitors; Molecular docking; Molecular dynamics; multicanonical Molecular Dynamics; Proteins; Solvation
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.26203

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 300 K 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 α‐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. Different representative binding configurations of a high‐affinity inhibitor to heat‐shock protein 90 predicted by our multicanonical molecular dynamics based dynamic docking simulations, where the top ranked one matches the experimental structure (root mean square deviation = 0.76 Å). Interestingly, the flexible lid region changed from a loop conformation in the experimental structure to a helical one in this structure, suggesting that even smaller ligands, such as we used here, can induce a conformational shift in this region in explicit solvent.