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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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Analysis of Essential Motions in the Closed and Open DnaK Forms.Functional dynamics maps and cross-correlation matrices of residue fluctuations for the ADP-bound DnaK structure (A, B) and ATP-bound DnaK form (C, D). Conformational dynamics profiles were computed by averaging protein motions in the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity of the protein residues. PCA computations are based on the Cα atoms. The axes denote Cα atoms of the protein residues in sequential order. Cross-correlations of residue-based fluctuations vary between +1 (fully correlated motion; fluctuation vectors in the same direction, colored in red) and -1 (fully anti-correlated motions; fluctuation vectors in the same direction, colored in blue). The residue ranges corresponding to the NBD, SBD-α, and SBD-β regions are highlighted.
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pone.0143752.g004: Analysis of Essential Motions in the Closed and Open DnaK Forms.Functional dynamics maps and cross-correlation matrices of residue fluctuations for the ADP-bound DnaK structure (A, B) and ATP-bound DnaK form (C, D). Conformational dynamics profiles were computed by averaging protein motions in the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity of the protein residues. PCA computations are based on the Cα atoms. The axes denote Cα atoms of the protein residues in sequential order. Cross-correlations of residue-based fluctuations vary between +1 (fully correlated motion; fluctuation vectors in the same direction, colored in red) and -1 (fully anti-correlated motions; fluctuation vectors in the same direction, colored in blue). The residue ranges corresponding to the NBD, SBD-α, and SBD-β regions are highlighted.

Mentions: Principal component analysis (PCA) of simulation trajectories in the essential space of low frequency modes clarified differences in global collective motions of these chaperones. In the DnaK structures, the NBD subdomains were not excessively rigid, and the subdomain IIB along with the SBD-β substrate binding loops was quite flexible (Fig 4A and 4B). Functional dynamics maps of residue cross-correlations showed an appreciable coupling of the NBD subdomains induced by ATP binding (Fig 4C and 4D). Another interesting observation was the emergence of positive cross-correlations between the SBD-α and SBD-β residues in the ATP-bound DnaK. As a result, cooperative motions of the SBD subdomains may promote stability of the NBD-SBD interactions and enable nucleotide-dependent allostery in DnaK. Subtle but important differences in functional dynamics emerged from simulations of the ATP-bound Sse1p structures (Fig 5). We noticed that structural core of Sse1p, most notably the NBD subdomains, may become exceedingly rigid. Furthermore, movements of the SBD-α and SBD-β subdomains may become increasingly decoupled, owing to a contrasted pattern of rigidity and flexibility of stably bound SBD-α and highly flexible substrate binding loops of the SBD-β (Fig 5A and 5B). A similar picture was observed in the Sse1p-hHsp70 complex, where the presence of bound hHsp70-NBD did not change the dynamics map of Sse1p (Fig 5C and 5D). We argue that differences in collective movements may be associated with allosteric scenarios that are adopted by DnaK and Sse1p chaperones.


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)

Analysis of Essential Motions in the Closed and Open DnaK Forms.Functional dynamics maps and cross-correlation matrices of residue fluctuations for the ADP-bound DnaK structure (A, B) and ATP-bound DnaK form (C, D). Conformational dynamics profiles were computed by averaging protein motions in the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity of the protein residues. PCA computations are based on the Cα atoms. The axes denote Cα atoms of the protein residues in sequential order. Cross-correlations of residue-based fluctuations vary between +1 (fully correlated motion; fluctuation vectors in the same direction, colored in red) and -1 (fully anti-correlated motions; fluctuation vectors in the same direction, colored in blue). The residue ranges corresponding to the NBD, SBD-α, and SBD-β regions are highlighted.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143752.g004: Analysis of Essential Motions in the Closed and Open DnaK Forms.Functional dynamics maps and cross-correlation matrices of residue fluctuations for the ADP-bound DnaK structure (A, B) and ATP-bound DnaK form (C, D). Conformational dynamics profiles were computed by averaging protein motions in the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity of the protein residues. PCA computations are based on the Cα atoms. The axes denote Cα atoms of the protein residues in sequential order. Cross-correlations of residue-based fluctuations vary between +1 (fully correlated motion; fluctuation vectors in the same direction, colored in red) and -1 (fully anti-correlated motions; fluctuation vectors in the same direction, colored in blue). The residue ranges corresponding to the NBD, SBD-α, and SBD-β regions are highlighted.
Mentions: Principal component analysis (PCA) of simulation trajectories in the essential space of low frequency modes clarified differences in global collective motions of these chaperones. In the DnaK structures, the NBD subdomains were not excessively rigid, and the subdomain IIB along with the SBD-β substrate binding loops was quite flexible (Fig 4A and 4B). Functional dynamics maps of residue cross-correlations showed an appreciable coupling of the NBD subdomains induced by ATP binding (Fig 4C and 4D). Another interesting observation was the emergence of positive cross-correlations between the SBD-α and SBD-β residues in the ATP-bound DnaK. As a result, cooperative motions of the SBD subdomains may promote stability of the NBD-SBD interactions and enable nucleotide-dependent allostery in DnaK. Subtle but important differences in functional dynamics emerged from simulations of the ATP-bound Sse1p structures (Fig 5). We noticed that structural core of Sse1p, most notably the NBD subdomains, may become exceedingly rigid. Furthermore, movements of the SBD-α and SBD-β subdomains may become increasingly decoupled, owing to a contrasted pattern of rigidity and flexibility of stably bound SBD-α and highly flexible substrate binding loops of the SBD-β (Fig 5A and 5B). A similar picture was observed in the Sse1p-hHsp70 complex, where the presence of bound hHsp70-NBD did not change the dynamics map of Sse1p (Fig 5C and 5D). We argue that differences in collective movements may be associated with allosteric scenarios that are adopted by DnaK and Sse1p chaperones.

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