Allosteric Modulation of Human Hsp90α Conformational Dynamics.

Area of Science:

• Structural Biology
• Molecular Dynamics
• Biophysics

Background:

• Heat shock protein 90 (Hsp90) is crucial for cellular protein homeostasis and implicated in various pathologies.
• Hsp90's function relies on conformational changes modulated by cochaperones and nucleotide binding.
• Targeting Hsp90's regulatory mechanisms offers a therapeutic strategy for Hsp90-associated diseases.

Purpose of the Study:

• To elucidate allosteric mechanisms and identify modulation sites in human Hsp90α using computational methods.
• To understand the role of nucleotide binding (ATP/ADP) in Hsp90 conformational dynamics.
• To investigate intraprotein communication pathways and identify key residues involved in conformational transitions.

Main Methods:

• Homology modeling to generate full-length human Hsp90α structures in closed and partially open states.
• Atomistic molecular dynamics simulations to analyze conformational dynamics and stability.
• Dynamic residue network analysis and perturbation response scanning to identify communication hubs and allosteric sites.

Main Results:

• Adenosine triphosphate (ATP) binding stabilizes the Hsp90 dimer, while adenosine diphosphate (ADP) and apo states increase flexibility, leading to a 'v-like' open conformation.
• Dynamic residue network analysis identified key communication hubs correlating with known functional sites.
• Perturbation response scanning revealed potential allosteric sites that overlap with known cochaperone (Aha1) and client binding sites in the ATP-bound state.

Conclusions:

• Nucleotide binding allosterically modulates Hsp90 conformational dynamics, influencing protein stability and flexibility.
• Shortest path and betweenness centrality are proposed as more relevant metrics than residue fluctuations for identifying functional residues.
• Identified allosteric sites offer potential targets for therapeutic intervention in Hsp90-associated diseases.