Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2
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{"title"=>"Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2", "type"=>"journal", "authors"=>[{"first_name"=>"Juan A.", "last_name"=>"Bueren-Calabuig", "scopus_author_id"=>"26537028600"}, {"first_name"=>"Julien", "last_name"=>"Michel", "scopus_author_id"=>"15520146800"}], "year"=>2015, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"15537358", "sgr"=>"84940467577", "doi"=>"10.1371/journal.pcbi.1004282", "pmid"=>"26046940", "scopus"=>"2-s2.0-84940467577", "pui"=>"607497662"}, "id"=>"50501bd5-123b-3035-b3ae-9c71021e050e", "abstract"=>"Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2.", "link"=>"http://www.mendeley.com/research/elucidation-liganddependent-modulation-disorderorder-transitions-oncoprotein-mdm2", "reader_count"=>26, "reader_count_by_academic_status"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Master"=>2, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Master"=>2, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>9, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Physics and Astronomy"=>1, "Chemistry"=>10}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>10}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"India"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2097272"], "description"=>"<p>(A) The exchange between open and closed states of the lid (1–24, in green) takes place over a 10-ms time-scale.[<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref011\" target=\"_blank\">11</a>–<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref015\" target=\"_blank\">15</a>,<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref018\" target=\"_blank\">18</a>] In the closed state, the lid occupies the p53-binding pocket in the MDM2 core region (25–119, in blue). The structures are representative snapshots from the umbrella sampling simulations. (B) Structure of p53 TAD (17–29) and chemical structures of three small molecule MDM2 ligands: Nutlin-3a, 1,4-benzodiazepine-2,5-dione (Bzd) and Piperidinone-2 (Pip2). Fold-improvements in binding affinity between lid containing MDM2 constructs (MDM2 (2–118) for Nutlin-3a and Pip2, MDM2 (2–188) for Bzd) and lid-less constructs (MDM2 (17–125)) are quoted below each structure and are derived from K<sub>d</sub> data from Michelsen et al.[<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref024\" target=\"_blank\">24</a>] (isothermal titration calorimetry assay) and Parks et al.[<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref025\" target=\"_blank\">25</a>] (fluorescence polarization assay).</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437959, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_N_terminal_domain_of_apo_MDM2_residues_1_8211_119_displaying_several_lid_conformations_and_four_representative_MDM2_binders_/1437959", "title"=>"N-terminal domain of apo-MDM2 (residues 1–119) displaying several lid conformations and four representative MDM2 binders.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097275"], "description"=>"<p>Free energy contours (kcal mol<sup>-1</sup>) are shown as a color coded heat map. Free energies are relative to the lowest free energy bin and are shown up to 12 kcal mol<sup>-1</sup> above the lowest free energy bin. For every system, representative structures of MDM2 displaying 10 lid conformations from selected bins are shown. A) apo MDM2. B) p53-TAD(17–29)/MDM2 C) Nutlin-3a/MDM2 D) Bzd/MDM2 E) Pip2/MDM2. The lid conformation seen in the x-ray structure of MDM2 (6–125) reported by Michelsen et al. is shown in red cartoon representation [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref024\" target=\"_blank\">24</a>].</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437962, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_dependent_modulation_of_MDM2_lid_free_energy_landscapes_CV1_lid_extension_in_197_and_CV2_lid_core_angle_in_degrees_/1437962", "title"=>"Ligand-dependent modulation of MDM2 lid free energy landscapes. CV1 (lid extension) in Å, and CV2 (lid-core angle) in degrees.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097359", "https://ndownloader.figshare.com/files/2097360", "https://ndownloader.figshare.com/files/2097361", "https://ndownloader.figshare.com/files/2097362", "https://ndownloader.figshare.com/files/2097363", "https://ndownloader.figshare.com/files/2097364", "https://ndownloader.figshare.com/files/2097365", "https://ndownloader.figshare.com/files/2097366", "https://ndownloader.figshare.com/files/2097367", "https://ndownloader.figshare.com/files/2097368"], "description"=>"<div><p>Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2.</p></div>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1438028, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1004282.s001", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s002", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s003", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s004", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s005", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s006", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s007", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s008", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s009", "https://dx.doi.org/10.1371/journal.pcbi.1004282.s010"], "stats"=>{"downloads"=>31, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Elucidation_of_Ligand_Dependent_Modulation_of_Disorder_Order_Transitions_in_the_Oncoprotein_MDM2_/1438028", "title"=>"Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097283"], "description"=>"<p>Left) per-lid residue average backbone RMSD. Right) Backbone RMSD over full lid (green) or core (blue) regions. From top to bottom, A) apo MDM2, B) p53-bound MDM2, C) Nutlin-3a-bound MDM2, D) Bzd-bound MDM2, E) Pip2-bound MDM2.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437965, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g003", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_dependent_modulation_of_MDM2_lid_flexibility_/1437965", "title"=>"Ligand-dependent modulation of MDM2 lid flexibility.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097285"], "description"=>"<p>Red: helix; Green: Turn; Yellow: β-Strand. Black: Coil. Secondary structure definitions follow the DSSP code [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref034\" target=\"_blank\">34</a>]. From top to bottom, A) apo MDM2, B) p53-bound MDM2, C) Nutlin-3a-bound MDM2, D) Bzd-bound MDM2, E) Pip2-bound MDM2.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437967, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g004", "stats"=>{"downloads"=>2, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_dependent_modulation_of_MDM2_lid_secondary_structure_propensity_/1437967", "title"=>"Ligand-dependent modulation of MDM2 lid secondary structure propensity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097287"], "description"=>"<p>A) NMR ensemble of apo MDM2 lid (1–24) from Uhrinova et al [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref019\" target=\"_blank\">19</a>]. B) crystal structure of Pip2-MDM2 lid (6–24) from Michelsen et al.[<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref024\" target=\"_blank\">24</a>]. Red: helix; Green: Turn; Yellow: β-Strand. Black: Coil.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437969, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g005", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Secondary_structure_propensity_of_the_lid_region_from_experimental_methods_/1437969", "title"=>"Secondary structure propensity of the lid region from experimental methods.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097290"], "description"=>"<p>Lid-core hydrophobic contacts are displayed in red; lid-ligand hydrophobic contacts are displayed in orange; lid-lid hydrophobic contacts are displayed in maroon. Lid-core hydrogen bonds are displayed in dark blue; lid-ligand hydrogen bonds are displayed in light blue; lid-lid hydrogen bonds are displayed in green. From top to bottom, A) apo MDM2, B) p53-bound MDM2, C) Nutlin-3a-bound MDM2, D) Bzd-bound MDM2, E) Pip2-bound MDM2.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437972, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g006", "stats"=>{"downloads"=>4, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_dependent_modulation_of_MDM2_lid_intermolecular_and_intramolecular_interactions_/1437972", "title"=>"Ligand-dependent modulation of MDM2 lid intermolecular and intramolecular interactions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097293"], "description"=>"<p>A) Apo-MDM2. Structural ensemble (A1) and structural details of the closed (A2) and open states (A3). B) p53-MDM2 complex. Structural ensemble (B1) and structural details (B2). C) Nutlin3a-MDM2 complex. Structural ensemble (C1) and structural details (C2). D) Bzd-MDM2 complex. Structural ensemble (D1) and structural details (D2). E). Pip2-MDM2 complex. Structural ensemble (E1) and structural details (E2). The X-ray structure of Pip2-MDM2 from Michelsen et al. is shown in red cartoon.[<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref024\" target=\"_blank\">24</a>] Representatives PDB files are included in the Supporting Information.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437975, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g007", "stats"=>{"downloads"=>5, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MDM2_lid_structural_ensembles_and_contact_details_from_representative_structures_for_the_five_systems_studied_/1437975", "title"=>"MDM2 lid structural ensembles and contact details from representative structures for the five systems studied.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097298"], "description"=>"<p>Top) Lid-core hydrophobic contacts are displayed in red and lid-ligand hydrophobic contacts, in orange. Lid-core hydrogen bonds are shown in dark blue and lid-ligand hydrogen bonds in light blue. Bottom) Lid-lid hydrophobic contacts are displayed in maroon. Lid-lid hydrogen bonds are displayed in green.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437977, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g008", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MDM2_lid_intermolecular_and_intramolecular_interactions_observed_in_the_Pip2_MDM2_crystal_structure_of_Michelsen_et_al_24_/1437977", "title"=>"MDM2 lid intermolecular and intramolecular interactions observed in the Pip2-MDM2 crystal structure of Michelsen et al [24].", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097300"], "description"=>"<p>A) Ensemble average of lid-ligand interaction energies <i>E</i><sub><i>lig-lid</i></sub> = <<i>E</i><sub><i>lig-lid</i></sub>>. B) Changes in ensemble average of lid-core interaction energies Δ<i>E</i><sub><i>lid-core</i></sub> = <<i>E</i><sub><i>lid-core</i>,<i>holo</i></sub>>—<<i>E</i><sub><i>lid-core</i>,<i>apo</i></sub>>. C) Changes in ensemble average of lid-lid interaction energies Δ<i>E</i><sub><i>lid-lid</i></sub> = <<i>E</i><sub><i>lid-lid</i>,<i>holo</i></sub>>—<<i>E</i><sub><i>lid-lid</i>,<i>apo</i></sub>>. Lennard-Jones energies are depicted in red, Coulombic energies in blue, and total interaction energies in gray. Energies are shown in kcal.mol<sup>-1</sup>.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437979, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g009", "stats"=>{"downloads"=>3, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impact_of_ligand_binding_on_MDM2_lid_energetics_/1437979", "title"=>"Impact of ligand binding on MDM2 lid energetics.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097301"], "description"=>"<p>CV1: lid extension (Met1(Cα)-Glu23(Cα) distance); CV2: lid-core angle (Met62(Cα)-Met50(Cα)-Asp11(Cα).</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437980, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.g010", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Definition_of_the_collective_variables_used_during_the_US_simulations_of_the_MDM2_lid_dynamics_/1437980", "title"=>"Definition of the collective variables used during the US simulations of the MDM2 lid dynamics.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-05 02:55:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2097302"], "description"=>"<p>The choice of the parameters was initially done using according to guidelines from Bucher et al. [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref068\" target=\"_blank\">68</a>] and Pierce et al. [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004282#pcbi.1004282.ref067\" target=\"_blank\">67</a>], and further adjustments were done with the help of preliminary cMD simulations. All the parameters are given in kcal.mol<sup>-1</sup>.</p><p>aMD parameters used in the present simulations.</p>", "links"=>[], "tags"=>["lid states", "solubilizing groups", "umbrella sampling", "tad", "lid region", "novel combination", "energy profile methodologies", "protein regions", "ligand", "protein region", "biomolecular interactions", "benzodiazepinedione inhibitors", "drug design", "piperidinone family", "MDM 2 lid region", "apo MDM 2.", "lid correlates", "oncoprotein MDM 2", "ensemble", "affinity improvement", "Mdm 2", "NMR measurements"], "article_id"=>1437981, "categories"=>["Biological Sciences"], "users"=>["Juan A. Bueren-Calabuig", "Julien Michel"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004282.t001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_aMD_parameters_used_in_the_present_simulations_/1437981", "title"=>"aMD parameters used in the present simulations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-05 02:55:14"}

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  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"2", "full-text"=>"0", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"9", "full-text"=>"11", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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