Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

Understanding how local protein modifications, such as binding
small-molecule ligands, can trigger and regulate large-scale motions of
large protein domains is a major open issue in molecular biology. We
address various aspects of this problem by analyzing and comparing
atomistic simulations of Hsp90 family representatives for which crystal
structures of the full length protein are available: mammalian Grp94,
yeast Hsp90 and E. coli HtpG. These chaperones are studied in complex
with the natural ligands ATP, ADP and in the Apo state. Common key
aspects of their functional dynamics are elucidated with a novel
multi-scale comparison of their internal dynamics. Starting from the
atomic resolution investigation of internal fluctuations and geometric
strain patterns, a novel analysis of domain dynamics is developed. The
results reveal that the ligand-dependent structural modulations mostly
consist of relative rigid-like movements of a limited number of
quasi-rigid domains, shared by the three proteins. Two common primary
hinges for such movements are identified. The first hinge, whose
functional role has been demonstrated by several experimental
approaches, is located at the boundary between the N-terminal and
Middle-domains. The second hinge is located at the end of a three-helix
bundle in the Middle-domain and unfolds/unpacks going from the ATP- to
the ADP-state. This latter site could represent a promising novel
druggable allosteric site common to all chaperones.