Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study
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{"title"=>"Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study", "type"=>"journal", "authors"=>[{"first_name"=>"Kristin", "last_name"=>"Blacklock"}, {"first_name"=>"Gennady M.", "last_name"=>"Verkhivker"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"563050629", "sgr"=>"84888606976", "issn"=>"1932-6203", "pmid"=>"23977182", "scopus"=>"2-s2.0-84888606976", "doi"=>"10.1371/journal.pone.0071936", "isbn"=>"1932-6203"}, "id"=>"dcf82209-7a6a-399d-95f0-bc6d00e8dce9", "abstract"=>"Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide \"molecular brakes\" that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity and direct the chaperone cycle by exerting the precise control over structural stability, global movements and allosteric communications in Hsp90.", "link"=>"http://www.mendeley.com/research/differential-modulation-functional-dynamics-allosteric-interactions-hsp90cochaperone-complexes-p23-a", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>1, "Chemistry"=>5, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}}, "reader_count_by_country"=>{"Czech Republic"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1173723"], "description"=>"<p>Clockwise from top left, ATP binding to the Hsp90-N domain of apo-HSP90 induces a conformational change and the closure of the ATP lid leading to a “semi-closed” state with twisted subunits and partly separated Hsp90-N domains. This state is illustrated by using a twisted conformation of the mammalian Grp94 homologue from the crystal structure complex with AMP-PNP (PDB ID 2O1U) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Dollins1\" target=\"_blank\">[40]</a>. The unbound form of the chaperone is depicted by using the crystal structure of the bacterial homologue HtpG in an apo-form (PDB ID 2IOQ) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Shiau1\" target=\"_blank\">[39]</a>. After lid closure, Aha1 accelerates the ATPase cycle facilitating dimerization process of the Hsp90-N domains and the formation of a partially closed state with the dynamically associated ATP. Binding of p23 displaces Aha1 and stabilizes the completely closed ATP-bound Hsp90 dimer in a hydrolysis-competent state. This conformation is committed for ATP hydrolysis. Both states are represented by the closed dimer conformation from the crystal structure of yeast Hsp90 bound to the AMP-PNP and p23 (mammals)/Sba1 (yeast homologue) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Ali1\" target=\"_blank\">[38]</a>. After ATP hydrolysis, p23 is released leading to a “semi-opened” ADP-bound state with the Hsp90-N domains partially separated. This functional state is presented by the crystal structure of an ADP-bound form of the bacterial homologue HtpG (PDB ID 2IOP) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Shiau1\" target=\"_blank\">[39]</a>. After ADP release, the substrate clients are released and the Hsp90-N domains dissociate leading to an open free form of the chaperone (pdb id 2IOQ). The Hsp90 structures are shown in surface representation and colored according to their domain nomenclature : N-terminal ATPase domain (Hsp90-N) that binds ATP is shown in green; a middle domain (Hsp90-M) that binds cochaperones and client proteins is shown in blue, and a C-terminal domain (Hsp90-C) required for dimerization is shown in red.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "cochaperones", "aha1", "p23", "hsp90-atpase"], "article_id"=>775456, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g001", "stats"=>{"downloads"=>5, "page_views"=>157, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Functional_Role_of_the_Cochaperones_Aha1_and_p23_in_the_Hsp90_ATPase_Cycle_/775456", "title"=>"The Functional Role of the Cochaperones Aha1 and p23 in the Hsp90-ATPase Cycle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173742"], "description"=>"<p>(Left Upper Panel) Structural distribution of conformational mobility in the Hsp90-Aha1 complex was obtained from the functional dynamics analysis. A ribbon-based protein representation with a background transparent surface view is employed. The Hsp90 residues from the intermolecular interface are colored according to their mobility (blue to light blue spheres). For clarity of presentation, the Aha1-N domain is shown in green ribbons, the Aha1-C domain in red ribbons. The Aha1-N and Aha1-C interfacial residues are shown respectively in green and red spheres. (Lower Left Panel) An overview of the Aha1-C binding interface. The Hsp90-N is shown in blue ribbons with the interfacial residues in blue spheres. The Aha1-C is shown in red ribbons and the interfacial residues are indicated by red spheres. (Right Panel) A detailed close-up of the Aha1-C interactions with the Hsp90-N domain. The interacting residues in the Hsp90-N included N164, E165, and R166 residues (shown in blue spheres). The interacting residues in the human Aha1-C are K273, P280, H283, A285, and T286 (shown in red spheres). The corresponding residues in the yeast Aha1-C are H284, S291, F294, S296, T297 are also annotated.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "aha1-c", "interactions"], "article_id"=>775469, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g009", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_and_Dynamic_Mapping_of_the_Aha1_C_Interactions_with_Hsp90_/775469", "title"=>"Structural and Dynamic Mapping of the Aha1-C Interactions with Hsp90.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173762", "https://ndownloader.figshare.com/files/1173763", "https://ndownloader.figshare.com/files/1173764", "https://ndownloader.figshare.com/files/1173765"], "description"=>"<div><p>Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide “molecular brakes” that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity and direct the chaperone cycle by exerting the precise control over structural stability, global movements and allosteric communications in Hsp90.</p></div>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "modulation", "allosteric", "interactions", "hsp90-cochaperone", "complexes", "p23", "computational"], "article_id"=>775488, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0071936.s001", "https://dx.doi.org/10.1371/journal.pone.0071936.s002", "https://dx.doi.org/10.1371/journal.pone.0071936.s003", "https://dx.doi.org/10.1371/journal.pone.0071936.s004"], "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_Modulation_of_Functional_Dynamics_and_Allosteric_Interactions_in_the_Hsp90_Cochaperone_Complexes_with_p23_and_Aha1_A_Computational_Study_/775488", "title"=>"Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173737"], "description"=>"<p>The predicted low-energy model of the Aha1-N domain bound to the Hsp90 dimer is shown in (A) in a sphere-based protein representation. The Hsp90 dimer is shown in grey spheres, the docked Aha1-N domain is colored in red spheres. The best low-energy models of the Aha1-N complexes obtained in the initial analysis (panels A and D in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936.s001\" target=\"_blank\">Figure S1</a>) were optimized in additional rounds of the HADDOCK and MD refinement. The intermolecular AIR was supplemented by the intramolecular constraints to preserve secondary structures in the Aha1-N during semi-flexible stages of HADDOCK refinement. These intramolecular interactions were formatted into a distance restraint file and uploaded to HADDOCK as unambiguous interaction restraints. (B) Superposition of the predicted structural model of the Aha1-N complex in the dimer with the crystal structure of the Aha1-N complex with the Hsp90-M (PDB ID 1USU) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Meyer2\" target=\"_blank\">[66]</a>. The docked Aha1-N domain is shown in red ribbons and the Hsp90-M domain of the chaperone dimer is in green ribbons. The crystal structure of the Aha1-N domain bound to the Hsp90-M domain is shown in blue ribbons. The structure of the Hsp90 dimer is enclosed in a 40% transparent molecular surface colored in green.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "aha1-n", "hsp90"], "article_id"=>775465, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g007", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Predicted_Model_of_the_Aha1_N_Domain_Complex_with_Hsp90_Dimer_/775465", "title"=>"The Predicted Model of the Aha1-N Domain Complex with Hsp90 Dimer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173733"], "description"=>"<p>The cross-correlation matrices of residue fluctuations computed along the low frequency modes in the ATP-bound Hsp90 dimer (A) and in the Hsp90-p23 complex (B). The matrix was calculated using the results of MD-based refinement and NMA of the predicted structures. The essential directions of correlated motions during dynamics were then calculated by diagonalizing the covariance matrix. 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 values above 0.5 are colored in dark red and the lower bound in the color bar indicates the value of the most anti-correlated pairs. Bottom panels: The Hsp90 structure is shown in a ribbon representation (Hsp90-N in green, Hsp90-M in blue, and Hsp90-C in red). The p23 molecules (right bottom panel) are shown in black ribbons. The residue indexing of the Hsp90 domains as used in the cross-correlation matrices is indicated. In the original crystal structure of yeast Hsp90 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Ali1\" target=\"_blank\">[38]</a> the domain annotation for the monomer 1 is: Hsp90-N (residues 2–216), Hsp90-M (residues 262–329, 339–526) and Hsp90-C (residues 527–597, 611–677). In the monomer 2 Hsp90-N (residues 2–216), Hsp90-M (residues 262–526) and Hsp90-C (527–597, 611–677). The structurally unresolved residues are 217–261, 330–338 (only in the first monomer), and 598–610. The crystal structure was employed as a starting point for the simulations. The disordered charged loop between the Hsp90-N and Hsp90-M domains was replaced by a modeled Gly-based linker using the ModLoop server <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Fiser1\" target=\"_blank\">[140]</a>. All disordered loops in the Hsp90-M and Hsp90-C domain were modeled with ModLoop by preserving the original protein sequence. The original crystallographic annotation was converted to a consecutive numbering in the cross-correlation matrix where the adjusted domain annotation is as following. The monomer 1 includes residues 1–641 and the monomer 2 consists of residues 642–1282. In the monomer 1: Hsp90-N (residues 1–215), Hsp90-M (residues 216–490) and Hsp90-C (residues 491–641). In the monomer 2: Hsp90-N (residues 642–856), Hsp90-M (residues 857–1131), and Hsp90-C (residues 1132–1282). The p23 residues are 1283–1406 (molecule 1) and 1407–1530 (molecule 2) respectively.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "comparative", "correlated", "motions", "atp-bound", "hsp90", "hsp90-p23"], "article_id"=>775463, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g005", "stats"=>{"downloads"=>4, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Comparative_Analysis_of_Correlated_Motions_in_the_ATP_bound_Hsp90_and_the_ATP_bound_Hsp90_p23_Complex_/775463", "title"=>"A Comparative Analysis of Correlated Motions in the ATP-bound Hsp90 and the ATP-bound Hsp90-p23 Complex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173735"], "description"=>"<p>The distributions of allosterically communicating residues are shown in a sphere-based residue representation for the ATP-bound form of Hsp90 (A) and in the Hsp90-p23 complex (B). These distributions are mapped onto respective functional dynamics profiles of Hsp90 shown in a surface-based protein representation. The color gradient from blue to red indicates the decreasing structural rigidity of protein residues similar to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone-0071936-g004\" target=\"_blank\">Figure 4</a>. The crystal structure of yeast Hsp90 is enveloped in a 50% transparent molecular surface to show the location of the allosterically communicating residues. The location and identity of allosterically communicating residues are annotated and the Hsp90 domains are indicated. The effectively communicating clusters included the Hsp90-N residues (T22, A41, G81, G121, G170, 207-LVVT-210), the Hsp90-M residues (357-LIPE-360, 379-SRE-381, 426-KLG-428, 479-LKAVE-481) and the Hsp90-C residues (576-AAIRTG-581). The changes in the distribution of allosterically interacting residues induced by p23 binding are depicted (B). The close proximity of these residues to the three-helix bundle (shown in ribbon representation) that links the inter-domain regions can be also seen.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "comparative", "allosterically", "communicating"], "article_id"=>775464, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g006", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Comparative_Analysis_of_the_Allosterically_Communicating_Networks_/775464", "title"=>"A Comparative Analysis of the Allosterically Communicating Networks.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173730"], "description"=>"<p>Structural distribution of conformational mobility in the ATP-bound form of yeast Hsp90 (A) and the Hsp90-p23 complex (B) was averaged over three lowest frequency modes obtained from the functional dynamics analysis. A close-up view of the protein mobility profiles for a panel of Ile residues probed in the Ile-targeted NMR experiments of the Hsp90-p23 complex <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Karagz1\" target=\"_blank\">[56]</a>. These residues were mapped onto the crystal structure of yeast Hsp90 (PDB ID 2CG9) and depicted in colored spheres according to their mobility. A surface-based protein representation is employed. The color gradient from blue to red indicates the decreasing structural rigidity (or increasing conformational mobility) of protein residues. The numbering of the Ile-probed residues corresponds to the crystal structure of yeast Hsp90. The highlighted Ile residues in yeast Hsp90 (I12, I19, I20, I45, I66, I82, I358, I388, V429, and I471) correspond to the Ile-probed residues in human Hsp90β (I20, I27, I28, I53, I75, I90, I369, I399, I440, and I482 respectively <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Karagz1\" target=\"_blank\">[56]</a>). The three-helix bundle that links the inter-domain N-M and M-C regions and coordinates motions of the regulatory hinges is shown in ribbon representation. The unrelated obstructing features in the foreground were omitted for clarity. The Pymol program was used for visualization of the protein structures (The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, and LLC).</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "conformational", "mobility", "profiles", "atp-bound", "hsp90", "dimer", "hsp90-p23"], "article_id"=>775462, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g004", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_Dynamics_and_Conformational_Mobility_Profiles_of_the_ATP_bound_Hsp90_Dimer_and_the_Hsp90_p23_Complex_/775462", "title"=>"Functional Dynamics and Conformational Mobility Profiles of the ATP-bound Hsp90 Dimer and the Hsp90-p23 Complex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173749"], "description"=>"<p>The NMSF profiles of the Hsp90 residues were computed along the lowest frequency mode (A, B) and by averaging the residues fluctuations over 10 low frequency modes (C, D). The NMSF profiles of the unbound Hsp90 (in blue) and in the bound Hsp90 form (in red) are shown for the predicted complex with the Aha1-N domain (A,C) and the complex with a complete Aha1 molecule (B,D). The differences in the NMSF profile of Hsp90 induced by Aha1 binding were spread through multiple chaperone domains. The low-frequency motions of the inter-domain regions around hinge motifs are considerably curtailed. Functional movements of the Hsp90-N in the first monomer towards structurally rigid Hsp90-N in the second monomer could be induced by Aha1 binding. The crystal structure residue numbering was converted to a consecutive numbering as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone-0071936-g003\" target=\"_blank\">Figure 3</a>. The annotation for the monomer 1 of Hsp90 is the following: Hsp90-N (residues 1–215), Hsp90-M (residues 216–471) and Hsp90-C (residues 472–609). The annotation for the monomer 2 of Hsp90: Hsp90-N (residues 610–824), Hsp90-M (residues 825–1089), and Hsp90-C (residues 1090–1227).</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "residue-based", "fluctuation", "profiles", "aha1"], "article_id"=>775476, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g013", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Residue_Based_Fluctuation_Profiles_of_Hsp90_The_Effect_of_the_Aha1_Domains_/775476", "title"=>"The Residue-Based Fluctuation Profiles of Hsp90: The Effect of the Aha1 Domains.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173725"], "description"=>"<p>The homodimer architecture of the full-length Hsp9p0 dimer is illustrated by the crystal structure of a closed ATP-bound conformation of yeast Hsp90 dimer <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Ali1\" target=\"_blank\">[38]</a>. The structure is shown in a ribbon representation with a detailed annotation of structural elements (left panel) and in a general surface-based protein representation (right panel). The Hsp90-N domain is shown in green; the Hsp90-M domain is depicted in blue and the Hsp90-C domain is presented in red. Left Panel: The ATP lid residues 95–123 are shown in black (95-TIAKSGTKAFMEALSAGADVSMIGQFGVG-123). The catalytic loop residues (371-SEDLPLNLSREMLQQ-385) are shown in cyan with a key catalytic residue R-380 highlighted in cyan sticks. ATP molecule is colored by atoms and is shown in sticks. The three-helix bundle shown in blue ribbons (helix 1: residues 386–408; helix 2: residues 412–431; helix3: residues 435–442) links the inter-domain regions and the regulatory hinges. The N-M inter-domain hinge residues M382 and L383 are shown in cyan spheres; the M-C inter-domain hinge residues E402 and E406 are shown blue spheres. The cyan color of M382/L383 is according to the coloration of the catalytic loop (residues 371–385). The blue color of E402/E406 is according to the coloration of the Hsp90-M domain. In the original crystal structure of yeast Hsp90 the domain annotation for the monomer 1 is: Hsp90-N (residues 2–216), Hsp90-M (residues 262–329, 339–526) and Hsp90-C (residues 527–597, 611–677). In the monomer 2 Hsp90-N (residues 2–216), Hsp90-M (residues 262–526) and Hsp90-C (527–597, 611–677). The structurally unresolved residues are 217–261, 330–338 (only in the first monomer), and 598–610. The Pymol program was used for visualization of Hsp90 structures (The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, and LLC).</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "full-length", "hsp90"], "article_id"=>775458, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Structure_of_the_Full_Length_Hsp90_Dimer_/775458", "title"=>"The Structure of the Full-Length Hsp90 Dimer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173745"], "description"=>"<p>The functional dynamics profiles of the Hsp90-Aha1 complexes with the Aha1-N domain (A) and the complete Aha1 molecule (B). A ribbon-based representation of the Aha1 domains is combined with a surface view of the Hsp90 dimer. The color gradient from blue to red indicates the decreasing structural rigidity of protein residues as in previous figures. (C) The distribution of allosterically in the context of the functional dynamics profile. The location and identities of allosterically communicating residues are annotated in spheres colored according to their respective mobility level. The crystal structure of yeast Hsp90 is enveloped in a 50% transparent molecular surface to show the location of the allosterically communicating residues. The three-helix bundle that links the inter-domain regions is shown in ribbon representation.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "allosterically", "communicating", "residues", "hsp90-aha1"], "article_id"=>775472, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g011", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Allosterically_Communicating_Residues_in_the_Hsp90_Aha1_Complex_/775472", "title"=>"The Allosterically Communicating Residues in the Hsp90-Aha1 Complex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173759"], "description"=>"<p>The residue-based configurational frustration index values are shown for the ATP-bound, cochaperone-free form of the Hsp90 dimer: monomer 1 (A) and monomer 2 (B). The integrated analysis the configurational frustration at the contact level is shown in (C, D). The local frustration density counts the number of contacts in each of the frustration categories within 5 Å from a given residue, i.e. how many contacts of a given residue are minimally frustrated (green), neutral (blue) or highly frustrated (red). The frustration density is represented in terms of the total numbers in each frustration category rather than the fraction of contacts in each class. (C) The local frustration density of the cochaperone-free (C) and Aha1-complexed forms of Hsp90 (D).</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "profiles"], "article_id"=>775485, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g015", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Local_Frustration_Profiles_of_Hsp90_/775485", "title"=>"The Local Frustration Profiles of Hsp90.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173743"], "description"=>"<p>The cross-correlation matrices of residue fluctuations computed along the low frequency modes in the Hsp90 complex with the Aha1-N domain (A) and in the complete Hsp90-Aha1 complex (B). The matrix was calculated using the results of MD-based refinement and NMA of the predicted structures for the bound Aha1-N domain (A) and the complete Aha1 molecule (B). The original residue numbering in the crystal structure of yeast Hsp90 (PDB ID 2CG9) was converted to a consecutive numbering in the cross-correlation matrix of the Hsp90 dimer as described in the caption of <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone-0071936-g005\" target=\"_blank\">Figure 5</a>. The monomer 1 includes residues 1–641 and the monomer 2 consists of residues 642–1282. In the monomer 1: Hsp90-N (residues 1–215), Hsp90-M (residues 216–490) and Hsp90-C (residues 491–641). In the monomer 2: Hsp90-N (residues 642–856), Hsp90-M (residues 857–1131), and Hsp90-C (residues 1132–1282). The Aha1-N domain includes residues 1283–1413 and the Aha1-C domain residues are in the range 1414–1549 respectively.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "correlated", "motions", "hsp90-aha1"], "article_id"=>775470, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g010", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_Correlated_Motions_in_the_Hsp90_Aha1_Complexes_/775470", "title"=>"Analysis of Correlated Motions in the Hsp90-Aha1 Complexes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173757"], "description"=>"<p>The distribution of structural communities in the cochaperone-free ATP-bound Hsp90 (A), the Hsp90-p23 complex (B) and the Hsp90-Aha1 complex (C). The Hsp90 structures are shown in ribbon representation and colored according to their domain nomenclature : Hsp90-N in green, Hsp90-M in blue, and Hsp90-C in red. The Hsp90 residues that constitute structural communities are shown in spheres and colored according to their respective domains. The displayed networks correspond to structurally stable communities that remained intact in more than 75% of the simulation snapshots. The increased consolidation and integration of small communities into larger highly connected networks could be observed in the Hsp90-p23 (B) and Hsp90-Aha1 complexes (C). The number of residues-based cliques (D) and communities (E) in the Hsp90 structures obtained by averaging these parameters over MD trajectories of the crystal structure of yeast Hsp90 (PDB ID 2CG9) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Ali1\" target=\"_blank\">[38]</a>; the crystal structures of the bacterial homologue HtpG in an open free form (PDB ID 2IOQ); an ADP-bound form (PDB ID 2IOP) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Shiau1\" target=\"_blank\">[39]</a>, and MD refinement trajectories of the Hsp90-p23 and Hsp90-Aha1 complexes.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "hsp90"], "article_id"=>775484, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g014", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_Structure_Network_Analysis_of_the_Hsp90_Complexes_/775484", "title"=>"Protein Structure Network Analysis of the Hsp90 Complexes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173739"], "description"=>"<p>The predicted binding interface between the Aha1-N and the Hsp90 dimer is presented. (Left Panel) Structural distribution of conformational mobility in the Hsp90-Aha1 complex was obtained from the functional dynamics analysis. A ribbon-based protein representation is employed. The color gradient from blue to red indicates the decreasing structural rigidity of protein residues as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone-0071936-g004\" target=\"_blank\">Figure 4</a>. The Hsp90 dimer is also enveloped in a 50% transparent molecular surface. The Hsp90 residues from the intermolecular interface are colored according to their mobility (blue to light blue spheres). For clarity of presentation, the Aha1-N domain is shown in green ribbons, the Aha1-C domain in red ribbons. The Aha1-N and Aha1-C interfacial residues are shown respectively in green and red spheres. (Right Panel) A close-up of the Aha1-N binding interface. A ribbon-based protein representation with a 40% transparent molecular surface at the background is used. The interfacial Hsp90 residues are annotated and shown in spheres colored according to their mobility in the complex (from rigid/blue to flexible/red). The Aha1-N interfacial residues are shown in green spheres. Of notice, a central hydrophobic cluster formed by I64, L66 and F100 of the Aha1-N and L315, I388 and V391 from the Hsp90-M domains. A network of hydrogen between D53, D101, D68 and E97 from the Aha1-N and K387, K390, K394 and K398 of the Hsp90-M domains is recognized as a crucial stabilizing contributor of the Hsp90-Aha1 complex <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Meyer2\" target=\"_blank\">[66]</a>. The predicted interacting residues in the Hsp90-N are D132, N151, T157, K178, D179, and D180.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "aha1-n", "interactions"], "article_id"=>775466, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g008", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_and_Dynamic_Mapping_of_the_Aha1_N_Interactions_with_Hsp90_/775466", "title"=>"Structural and Dynamic Mapping of the Aha1-N Interactions with Hsp90.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173727"], "description"=>"<p>Three-body body docking simulations used as independent unbound molecules the ATP-bound form of the Hsp90 dimer and the crystallographic conformations of two p23 molecules. Superposition of the docked Hsp90-p23 complex and the crystal structure of yeast Hsp90 bound the AMP-PNP and p23. The crystal structure has revealed two cochaperone molecules bound to the closed dimer form of Hsp90. (A, B) Front and side views of the docked Hsp90-p23 complex. The Hsp90 structure (pdb id 2CG9) is shown in spheres; the Hsp90-N domain in green, the Hsp90-M domain in blue, and the Hsp90-C domain in red. To illustrate binding of p23 molecules in a depression area at the interface of the two Hsp90-N domains, the crystallographic conformations of p23 (in red) and the predicted lowest docked conformations (in cyan) are highlighted in ribbons. (C) Superposition of the predicted yeast Hsp90-p23 complex (in blue) with the docked p23 molecules in cyan and the crystal structure (in green) with the crystallographic p23 conformations in red.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "modeling", "hsp90-p23"], "article_id"=>775460, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g003", "stats"=>{"downloads"=>3, "page_views"=>39, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_Modeling_of_the_Hsp90_p23_Complex_/775460", "title"=>"Structural Modeling of the Hsp90-p23 Complex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1173747"], "description"=>"<p>(Left Upper Panel) Conformational mobility map of the Hsp90-Aha1 interactions with the Aha1-N and Aha1-C domains was compared with the NMR experiments <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Retzlaff1\" target=\"_blank\">[68]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071936#pone.0071936-Koulov1\" target=\"_blank\">[69]</a>. The annotated Hsp90 regions (in spheres colored according to their mobility) correspond to the residues that experienced significant chemical shift perturbations upon Aha1 binding. (Right Panel) A close-up of the predicted Aha1-N binding interface with the Hsp90-M and Hsp90-N domains. The Aha1-N domain is shown in ribbon representation. The Aha1-N binding region involves residues from the three-helix bundle (shown in ribbon representation). Binding of the Aha1-N domain could affect structural stability of the Hsp90-M residues located near the N-M hinge region including E312, G313, E316, L357, I358, L374, V368, V391, I392, N395 (Left Lower Panel) A close-up of the predicted Aha1-C binding interface with the Hsp90-N domain. The Ana1-C is shown in ribbon representation. The conformational mobility profiles of the Hsp90 residues that were affected by the Aha1-N and Aha1-C binding are annotated in colored spheres. The allosteric effect of Aha1 binding can rigidify the Hsp90-N residues W148, T159, N164, E165, F176, L177, K178, D179, H197 and F200.</p>", "links"=>[], "tags"=>["Computational biology", "Biophysic al simulations", "Macromolecular structure analysis", "Signaling networks", "Computer modeling", "oncology", "Basic cancer research", "biophysics", "Biomacromolecule-ligand interactions", "Biophysics simulations", "Biophysics theory", "Macromolecular assemblies", "Protein chemistry", "Statistical mechanics", "aha1-mediated", "conformational", "mobility"], "article_id"=>775474, "categories"=>["Information And Computing Sciences", "Medicine", "Physics", "Biological Sciences"], "users"=>["Kristin Blacklock", "Gennady M. Verkhivker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0071936.g012", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Aha1_Mediated_Effect_on_Conformational_Mobility_of_Hsp90_/775474", "title"=>"The Aha1-Mediated Effect on Conformational Mobility of Hsp90.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-19 01:40:55"}

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Relative Metric

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