Abstract
The Hsp90 protein complex is one of the most abundant molecular chaperone proteins that assists in folding of a variety of client proteins. During its functional cycle it undergoes large domain rearrangements coupled to the hydrolysis of ATP and association or dissociation of domain interfaces. In order to better understand the domain dynamics comparative Molecular Dynamics (MD) simulations of a sub-structure of Hsp90, the dimer formed by the middle (M) and C-terminal domain (C), were performed. Since this MC dimer lacks the ATP-binding N-domain it allows studying global motions decoupled from ATP binding and hydrolysis. Conventional (c)MD simulations starting from several different closed and open conformations resulted in only limited sampling of global motions. However, the application of a Hamiltonian Replica exchange (H-REMD) method based on the addition of a biasing potential extracted from a coarse-grained elastic network description of the system allowed much broader sampling of domain motions than the cMD simulations. With this multiscale approach it was possible to extract the main directions of global motions and to obtain insight into the molecular mechanism of the global structural transitions of the MC dimer.
Highlights
The 90 kDa heat-shock protein (Hsp90) is an essential molecular chaperon protein that plays a vital role in the folding process of several client proteins (Hunter and Poon, 1997; Mayer and Bukau, 1999; MacLean and Picard, 2003; Pratt and Toft, 2003; Prodromou and Pearl, 2003; Pratt et al, 2004)
The results indicate, firstly, that the elastic network model (ENM)-REMD method is an efficient multi-scale enhanced sampling technique offering improved sampling compared to regular Molecular Dynamics (MD) simulations
Comparative MD simulations starting from closed intermediate open and fully open conformations were used to investigate the global mobility of the MC dimer
Summary
The 90 kDa heat-shock protein (Hsp90) is an essential molecular chaperon protein that plays a vital role in the folding process of several client proteins (Hunter and Poon, 1997; Mayer and Bukau, 1999; MacLean and Picard, 2003; Pratt and Toft, 2003; Prodromou and Pearl, 2003; Pratt et al, 2004). It is found in bacteria as well as eukaryotes and is essential for cell viability and plays a pivotal role in many signaling and regulation pathways (Echeverría et al, 2011). Structures of a paralog, Grp, from the mammalian endoplasmic reticulum
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