Modeling Signal Propagation Mechanisms and Ligand-Based Conformational Dynamics of the Hsp90 Molecular Chaperone Full-Length Dimer

Hsp90 is a molecular chaperone essential for protein folding and
activation in normal homeostasis and stress response. ATP binding and
hydrolysis facilitate Hsp90 conformational changes required for client
activation. Hsp90 plays an important role in disease states,
particularly in cancer, where chaperoning of the mutated and
overexpressed oncoproteins is important for function. Recent studies
have illuminated mechanisms related to the chaperone function. However,
an atomic resolution view of Hsp90 conformational dynamics, determined
by the presence of different binding partners, is critical to define
communication pathways between remote residues in different domains
intimately affecting the chaperone cycle. Here, we present a
computational analysis of signal propagation and long-range
communication pathways in Hsp90. We carried out molecular dynamics
simulations of the full-length Hsp90 dimer, combined with essential
dynamics, correlation analysis, and a signal propagation model. All-atom
MD simulations with timescales of 70 ns have been performed for
complexes with the natural substrates ATP and ADP and for the unliganded
dimer. We elucidate the mechanisms of signal propagation and determine
``hot spots'' involved in interdomain communication pathways from the
nucleotide-binding site to the C-terminal domain interface. A
comprehensive computational analysis of the Hsp90 communication pathways
and dynamics at atomic resolution has revealed the role of the
nucleotide in effecting conformational changes, elucidating the
mechanisms of signal propagation. Functionally important residues and
secondary structure elements emerge as effective mediators of
communication between the nucleotide-binding site and the C-terminal
interface. Furthermore, we show that specific interdomain signal
propagation pathways may be activated as a function of the ligand. Our
results support a ``conformational selection model'' of the Hsp90
mechanism, whereby the protein may exist in a dynamic equilibrium
between different conformational states available on the energy
landscape and binding of a specific partner can bias the equilibrium
toward functionally relevant complexes.