Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution

Molecular switching and ligand-based modulation of the 90-kDa heat-shock
protein (Hsp90) chaperone activity may ultimately facilitate
conformational coupling to the ATPase cycle along with activation and
recruitment of the broad range of client proteins. We present an atomic
resolution analysis of the Hsp90 N-terminal domain (NTD) binding energy
landscape by simulating protein dynamics with a range of binding
partners. We show that the activity of the molecular chaperone may be
linked to (i) local folding-unfolding transitions and conformational
switching of the ``active site lid'' upon binding and (it) differences
in the underlying protein dynamics as a function of the binding partner.
This study suggests that structural plasticity of the Hsp90 NTD can be
exploited by the molecular chaperone machinery to modulate enhanced
structural rigidity during ATP binding and increased protein flexibility
as a consequence of the inhibitor binding. The present study agrees with
the experimental structural data and provides a plausible molecular
model for understanding mechanisms of modulation of molecular chaperone
activities by binding partners.