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

Abstract

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.

Exploiting Conformational Dynamics in Drug Discovery: Design of C-Terminal Inhibitors of Hsp90 with Improved Activities

“…Such residues span the dimerization core of the C-terminal domain and the C-terminal loops near the boundary of the M-domain. 6,32,33 …”

“…32,33 In our model, allosteric pathways are defined by the identification of distal residues that move coherently within the active site of a protein. Towards this objective, we defined the coordination propensity (CP) between any two residues within a protein as a function of their distance fluctuation.…”

Pharmacological Enhancement of α-Glucosidase by the Allosteric Chaperone N-acetylcysteine

“…27 This quantity reports on the variations of the local deformations of the residues' contact networks as a consequence of the changes in their respective local structural environment. This parameter thus reflects the extent of conformational changes throughout the protein structure in response to specific perturbations.…”

SPECTRUS: A Dimensionality Reduction Approach for Identifying Dynamical Domains in Protein Complexes from Limited Structural Datasets

“…The fact that these structural changes are typically of large amplitude and have a collective character (Tirion, 1996;Tama and Sanejouand, 2001;Delarue and Sanejouand, 2002;Pontiggia et al, 2008) has naturally posed the challenge of developing suitable methods for describing these rearrangements in terms of rigid-like displacements (rotations and translations) of a limited number of quasi-rigid domains (Hayward et al, 1997;Wriggers and Schulten, 1997;Hinsen, 1998;Kundu et al, 2004;Painter and Merritt, 2006;Aleksiev et al, 2009;Bernhard and Noé , 2010;Kirchner and Gü ntert, 2011;Morra et al, 2012;Romanowska et al, 2012). By these means, one can achieve a parsimonious identification of the few degrees of freedom that suffice to describe and explore the conformational space accessible to a given protein.…”

“…For instance, they can be used to extend the analysis of molecular dynamics (MD) trajectories beyond the linear superposition of essential dynamical spaces, precondition enhanced sampling techniques, and compare the functional dynamics of proteins with different degrees of sequence and structural similarity (Song and Jernigan, 2006;Micheletti, 2013;Zen et al, 2008;Morra et al, 2012). Other applications include the selection of a manageable parameter space for inferential or maximum-likelihood structure determination (Zhang et al, 2012;Scheres et al, 2007) as well as detecting the basic mechanical and assembly units of large macromolecular complexes, such as viral capsids (Freddolino et al, 2006;Roos et al, 2012;Snijder et al, 2013;Polles et al, 2013).…”