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Dancing through Life: Molecular Dynamics Simulations and Network-Centric Modeling of Allosteric Mechanisms in Hsp70 and Hsp110 Chaperone Proteins.

Stetz G, Verkhivker GM - PLoS ONE (2015)

Bottom Line: The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate-binding regions.We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications.This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America.

ABSTRACT
Hsp70 and Hsp110 chaperones play an important role in regulating cellular processes that involve protein folding and stabilization, which are essential for the integrity of signaling networks. Although many aspects of allosteric regulatory mechanisms in Hsp70 and Hsp110 chaperones have been extensively studied and significantly advanced in recent experimental studies, the atomistic picture of signal propagation and energetics of dynamics-based communication still remain unresolved. In this work, we have combined molecular dynamics simulations and protein stability analysis of the chaperone structures with the network modeling of residue interaction networks to characterize molecular determinants of allosteric mechanisms. We have shown that allosteric mechanisms of Hsp70 and Hsp110 chaperones may be primarily determined by nucleotide-induced redistribution of local conformational ensembles in the inter-domain regions and the substrate binding domain. Conformational dynamics and energetics of the peptide substrate binding with the Hsp70 structures has been analyzed using free energy calculations, revealing allosteric hotspots that control negative cooperativity between regulatory sites. The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate-binding regions. A smaller allosteric network in Hsp110 structures may elicit an entropy-driven allostery that occurs in the absence of global structural changes. We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications. The network-centric analysis of allosteric interactions has also established that centrality of functional residues could correlate with their sensitivity to mutations across diverse chaperone functions. This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones.

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Force Constant and Network Centrality Profiles of DnaK Forms.Residue-based force constant profiles and network centrality distributions for an ADP-bound DnaK form (A, B) and ATP-bound Dnak state (C, D). The profiles are annotated and colored according to the adopted scheme: IA (in blue), IB (in red), IIA (in green), IIB (in cyan), the inter-domain linker (in black), SBD-α (in magenta), and SBD-β (in orange). The residue-based dynamic profiles are annotated using the residue numbering in the solution structure of an ADP-bound DnaK, (pdb id 2KHO) and the crystal structure of an ATP-bound DnaK, (pdb id 4B9Q). The peaks of the force constant and centrality profiles corresponding to functionally important residues are indicated by arrows and annotated.
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pone.0143752.g011: Force Constant and Network Centrality Profiles of DnaK Forms.Residue-based force constant profiles and network centrality distributions for an ADP-bound DnaK form (A, B) and ATP-bound Dnak state (C, D). The profiles are annotated and colored according to the adopted scheme: IA (in blue), IB (in red), IIA (in green), IIB (in cyan), the inter-domain linker (in black), SBD-α (in magenta), and SBD-β (in orange). The residue-based dynamic profiles are annotated using the residue numbering in the solution structure of an ADP-bound DnaK, (pdb id 2KHO) and the crystal structure of an ATP-bound DnaK, (pdb id 4B9Q). The peaks of the force constant and centrality profiles corresponding to functionally important residues are indicated by arrows and annotated.

Mentions: Using conformational ensembles, we computed the average betweenness indices and considered sharp peaks in the residue centrality profiles as a guiding indicator for the identification of functional residues critical for allosteric regulation. Strikingly, the force constant and centrality profiles in the DnaK forms (Fig 11) revealed generally similar distribution patterns, with the corresponding peaks often pointing to the same residues. Moreover, functional residues that were characterized by high force constants typically exhibited high network centrality. Structural mapping of high force constant (high centrality) residues onto DnaK conformations (Fig 12A and 12B) further clarified their functional role. We observed that hinge sites with high network centrality may be involved in key inter-domain contacts and form an interaction network that may propagate allosteric signals. In the ADP-bound DnaK, both the force constant profile (Fig 11A) and the centrality distribution (Fig 11B) featured numerous local peaks that were broadly distributed across domains. The main peaks corresponded to residue clusters 140–151 (subdomain IA), residues 371–373 (subdomain IA3), linker residues 393–394, residues 413–417 (L2,3 loop), residues 440–444 (L4,5 loop) and residues 479–482 (L6,7 loop) (Fig 11A and 11B). These distributions pointed to two potential hinge sites: the first corresponded to the interface between IA and IIA subdomains, while the second one was situated at the border between structurally rigid subdomain IA and a more flexible linker region.


Dancing through Life: Molecular Dynamics Simulations and Network-Centric Modeling of Allosteric Mechanisms in Hsp70 and Hsp110 Chaperone Proteins.

Stetz G, Verkhivker GM - PLoS ONE (2015)

Force Constant and Network Centrality Profiles of DnaK Forms.Residue-based force constant profiles and network centrality distributions for an ADP-bound DnaK form (A, B) and ATP-bound Dnak state (C, D). The profiles are annotated and colored according to the adopted scheme: IA (in blue), IB (in red), IIA (in green), IIB (in cyan), the inter-domain linker (in black), SBD-α (in magenta), and SBD-β (in orange). The residue-based dynamic profiles are annotated using the residue numbering in the solution structure of an ADP-bound DnaK, (pdb id 2KHO) and the crystal structure of an ATP-bound DnaK, (pdb id 4B9Q). The peaks of the force constant and centrality profiles corresponding to functionally important residues are indicated by arrows and annotated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664246&req=5

pone.0143752.g011: Force Constant and Network Centrality Profiles of DnaK Forms.Residue-based force constant profiles and network centrality distributions for an ADP-bound DnaK form (A, B) and ATP-bound Dnak state (C, D). The profiles are annotated and colored according to the adopted scheme: IA (in blue), IB (in red), IIA (in green), IIB (in cyan), the inter-domain linker (in black), SBD-α (in magenta), and SBD-β (in orange). The residue-based dynamic profiles are annotated using the residue numbering in the solution structure of an ADP-bound DnaK, (pdb id 2KHO) and the crystal structure of an ATP-bound DnaK, (pdb id 4B9Q). The peaks of the force constant and centrality profiles corresponding to functionally important residues are indicated by arrows and annotated.
Mentions: Using conformational ensembles, we computed the average betweenness indices and considered sharp peaks in the residue centrality profiles as a guiding indicator for the identification of functional residues critical for allosteric regulation. Strikingly, the force constant and centrality profiles in the DnaK forms (Fig 11) revealed generally similar distribution patterns, with the corresponding peaks often pointing to the same residues. Moreover, functional residues that were characterized by high force constants typically exhibited high network centrality. Structural mapping of high force constant (high centrality) residues onto DnaK conformations (Fig 12A and 12B) further clarified their functional role. We observed that hinge sites with high network centrality may be involved in key inter-domain contacts and form an interaction network that may propagate allosteric signals. In the ADP-bound DnaK, both the force constant profile (Fig 11A) and the centrality distribution (Fig 11B) featured numerous local peaks that were broadly distributed across domains. The main peaks corresponded to residue clusters 140–151 (subdomain IA), residues 371–373 (subdomain IA3), linker residues 393–394, residues 413–417 (L2,3 loop), residues 440–444 (L4,5 loop) and residues 479–482 (L6,7 loop) (Fig 11A and 11B). These distributions pointed to two potential hinge sites: the first corresponded to the interface between IA and IIA subdomains, while the second one was situated at the border between structurally rigid subdomain IA and a more flexible linker region.

Bottom Line: The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate-binding regions.We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications.This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America.

ABSTRACT
Hsp70 and Hsp110 chaperones play an important role in regulating cellular processes that involve protein folding and stabilization, which are essential for the integrity of signaling networks. Although many aspects of allosteric regulatory mechanisms in Hsp70 and Hsp110 chaperones have been extensively studied and significantly advanced in recent experimental studies, the atomistic picture of signal propagation and energetics of dynamics-based communication still remain unresolved. In this work, we have combined molecular dynamics simulations and protein stability analysis of the chaperone structures with the network modeling of residue interaction networks to characterize molecular determinants of allosteric mechanisms. We have shown that allosteric mechanisms of Hsp70 and Hsp110 chaperones may be primarily determined by nucleotide-induced redistribution of local conformational ensembles in the inter-domain regions and the substrate binding domain. Conformational dynamics and energetics of the peptide substrate binding with the Hsp70 structures has been analyzed using free energy calculations, revealing allosteric hotspots that control negative cooperativity between regulatory sites. The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate-binding regions. A smaller allosteric network in Hsp110 structures may elicit an entropy-driven allostery that occurs in the absence of global structural changes. We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications. The network-centric analysis of allosteric interactions has also established that centrality of functional residues could correlate with their sensitivity to mutations across diverse chaperone functions. This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones.

Show MeSH
Related in: MedlinePlus