Gaussian Accelerated Molecular Dynamics Uncovers Binding Mechanism Differences Between Small-Molecule Inhibitors and Grp94/Hsp90α: Elucidating Small Molecules' Selectivity for Grp94

Key Points

• The aim is to explore the binding mechanisms of small-molecule inhibitors to Grp94 compared to Hsp90α.
• Utilized Gaussian accelerated molecular dynamics simulations to analyze binding interactions.
• Investigated structural differences between Grp94 and Hsp90α under various conditions.
• Examined the impact of inhibitors on protein folding processes.
• Identified distinct binding modes for small-molecule inhibitors towards Grp94 versus Hsp90α.
• Demonstrated enhanced selectivity of inhibitors for Grp94 with specific molecular interactions.
• Revealed critical structural features responsible for the selectivity of small molecules.