A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein
Publication Date
May 26, 2011
Journal
PLOS Computational Biology
Authors
Daniel Adriano Silva, Gregory R. Bowman, Alejandro Sosa Peinado & Xuhui Huang
Volume
7
Issue
5
Pages
e1002054
DOI
https://dx.plos.org/10.1371/journal.pcbi.1002054
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1002054
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/21637799
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102756
Europe PMC
http://europepmc.org/abstract/MED/21637799
Web of Science
000291015800028
Scopus
79958136745
Mendeley
http://www.mendeley.com/research/role-both-conformational-selection-induced-fit-ligand-binding-lao-protein
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CiteULike | Further Information

Mendeley | Further Information

{"title"=>"A role for both conformational selection and induced fit in ligand binding by the lao protein", "type"=>"journal", "authors"=>[{"first_name"=>"Daniel Adriano", "last_name"=>"Silva", "scopus_author_id"=>"57188924698"}, {"first_name"=>"Gregory R.", "last_name"=>"Bowman", "scopus_author_id"=>"24334008700"}, {"first_name"=>"Alejandro", "last_name"=>"Sosa-Peinado", "scopus_author_id"=>"6507213088"}, {"first_name"=>"Xuhui", "last_name"=>"Huang", "scopus_author_id"=>"55500171200"}], "year"=>2011, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-79958136745", "doi"=>"10.1371/journal.pcbi.1002054", "sgr"=>"79958136745", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "pmid"=>"21637799", "issn"=>"1553734X", "pui"=>"361907846"}, "id"=>"b1f79fb4-6e53-3d51-a2f1-9d428dcbfb93", "abstract"=>"Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Ornithine-binding (LAO) protein binds to its ligand. We show that our model can predict the bound state, binding free energy, and association rate with reasonable accuracy and then use the model to dissect the binding mechanism. In the past, this binding event has often been assumed to occur via an induced fit mechanism because the protein's binding site is completely closed in the bound state, making it impossible for the ligand to enter the binding site after the protein has adopted the closed conformation. More complex mechanisms have also been hypothesized, but these have remained controversial. Here, we are able to directly observe roles for both the conformational selection and induced fit mechanisms in LAO binding. First, the LAO protein tends to form a partially closed encounter complex via conformational selection (that is, the apo protein can sample this state), though the induced fit mechanism can also play a role here. Then, interactions with the ligand can induce a transition to the bound state. Based on these results, we propose that MSMs built from atomistic simulations may be a powerful way of dissecting ligand-binding mechanisms and may eventually facilitate a deeper understanding of allostery as well as the prediction of new protein-ligand interactions, an important step in drug discovery.", "link"=>"http://www.mendeley.com/research/role-both-conformational-selection-induced-fit-ligand-binding-lao-protein", "reader_count"=>129, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>44, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>39, "Student > Postgraduate"=>4, "Student > Master"=>13, "Other"=>3, "Student > Bachelor"=>9, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>44, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>39, "Student > Postgraduate"=>4, "Student > Master"=>13, "Other"=>3, "Student > Bachelor"=>9, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Agricultural and Biological Sciences"=>44, "Arts and Humanities"=>1, "Business, Management and Accounting"=>1, "Chemistry"=>30, "Computer Science"=>11, "Engineering"=>3, "Biochemistry, Genetics and Molecular Biology"=>15, "Nursing and Health Professions"=>1, "Mathematics"=>3, "Medicine and Dentistry"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Physics and Astronomy"=>12}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>12}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}, "Engineering"=>{"Engineering"=>3}, "Chemistry"=>{"Chemistry"=>30}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>44}, "Computer Science"=>{"Computer Science"=>11}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>15}}, "reader_count_by_country"=>{"Argentina"=>1, "Hong Kong"=>1, "United States"=>8, "China"=>4, "Japan"=>1, "United Kingdom"=>1, "Italy"=>1, "Germany"=>5, "Russia"=>1}, "group_count"=>8}

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  • {"files"=>["https://ndownloader.figshare.com/files/393010", "https://ndownloader.figshare.com/files/393022", "https://ndownloader.figshare.com/files/393031", "https://ndownloader.figshare.com/files/393051", "https://ndownloader.figshare.com/files/393067", "https://ndownloader.figshare.com/files/393078", "https://ndownloader.figshare.com/files/393086", "https://ndownloader.figshare.com/files/393100", "https://ndownloader.figshare.com/files/393115", "https://ndownloader.figshare.com/files/393121", "https://ndownloader.figshare.com/files/393125", "https://ndownloader.figshare.com/files/393130"], "description"=>"<div><p>Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Ornithine-binding (LAO) protein binds to its ligand. We show that our model can predict the bound state, binding free energy, and association rate with reasonable accuracy and then use the model to dissect the binding mechanism. In the past, this binding event has often been assumed to occur via an induced fit mechanism because the protein's binding site is completely closed in the bound state, making it impossible for the ligand to enter the binding site after the protein has adopted the closed conformation. More complex mechanisms have also been hypothesized, but these have remained controversial. Here, we are able to directly observe roles for both the conformational selection and induced fit mechanisms in LAO binding. First, the LAO protein tends to form a partially closed encounter complex via conformational selection (that is, the apo protein can sample this state), though the induced fit mechanism can also play a role here. Then, interactions with the ligand can induce a transition to the bound state. Based on these results, we propose that MSMs built from atomistic simulations may be a powerful way of dissecting ligand-binding mechanisms and may eventually facilitate a deeper understanding of allostery as well as the prediction of new protein-ligand interactions, an important step in drug discovery.</p> </div>", "links"=>[], "tags"=>["conformational", "induced", "ligand", "binding", "lao"], "article_id"=>137607, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.s001", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s002", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s003", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s004", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s005", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s006", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s007", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s008", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s009", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s010", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s011", "https://dx.doi.org/10.1371/journal.pcbi.1002054.s012"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Role_for_Both_Conformational_Selection_and_Induced_Fit_in_Ligand_Binding_by_the_LAO_Protein/137607", "title"=>"A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-05-26 02:06:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/770638"], "description"=>"<p>The ligand, Arginine, is shown in red.</p>", "links"=>[], "tags"=>["states", "ornithine-binding"], "article_id"=>441006, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_open_PDB_ID_2LAO_and_closed_PDB_ID_1LAF_states_of_the_Lysine_Arginine_Ornithine_binding_LAO_Protein_/441006", "title"=>"The open (PDB ID: 2LAO) and closed (PDB ID: 1LAF) states of the Lysine-, Arginine-, Ornithine-binding (LAO) Protein.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:16:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/770740"], "description"=>"<p><b>(a)</b> A snapshot from our simulations (red) achieves a 1.2 Å RMSD to the X-ray bound state (blue, PDB ID: 1LAF). The RMSD is computed from the protein Cα atoms that are within 8 Å to the center of mass of the ligand in the X-ray bound state (Residues 9–15, 17–19, 30, 50–53, 55–56, 67–74, 77, 83, 88, 90–92, 117–124, 141–143, 159–162, 164, 190–191 and 194–196). If all-protein Cα atoms are included the RMSD is 1.8 Å. <b>(b)</b> Free energy plot of the protein opening angle versus twisting angle. The bin size is (5°, 5°), and the interval between two adjacent contour levels is 0.5 KT. The green and blue crosses correspond to X-ray structures of the bound and apo conformations respectively. (c) Free energy plot of the opening angle versus the distance between the ligand and the binding site. The bin size is (1.5 Å, 5°), and interval between contour levels is 0.5 KT.</p>", "links"=>[], "tags"=>["bound", "MSM", "lao", "binding", "populated", "having", "equilibrium"], "article_id"=>441106, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_bound_state_of_our_MSM_for_LAO_binding_which_is_also_the_most_populated_state_having_an_equilibrium_population_of_74_9_/441106", "title"=>"The bound state of our MSM for LAO binding (which is also the most populated state, having an equilibrium population of 74.9%).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:18:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/770973"], "description"=>"<p>The flux was calculated using a greedy backtracking algorithm <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002054#pcbi.1002054-Voelz1\" target=\"_blank\">[31]</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002054#pcbi.1002054-E1\" target=\"_blank\">[66]</a> applied to a 54-state MSM generated with the SHC algorithm <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002054#pcbi.1002054-Huang1\" target=\"_blank\">[30]</a>. These pathways account for 35% of the total flux from unbound states to the bound state. The arrow sizes are proportional to the interstate flux. State numbers and their equilibrium population calculated from MSM are also shown. The conformational selection and induced pathways from the unbound states to the encounter complex state is shown in green and grey arrows respectively.</p>", "links"=>[], "tags"=>["10", "highest", "flux", "pathways", "unbound", "states", "bound"], "article_id"=>441339, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Superposition_of_the_10_highest_flux_pathways_from_the_unbound_states_to_the_bound_state_/441339", "title"=>"Superposition of the 10 highest flux pathways from the unbound states to the bound state.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:22:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/771058"], "description"=>"<p>The green and blue crosses correspond to X-ray structures of the bound and apo conformations respectively. The bin size is (5°, 5°), and the interval between contour levels is 0.5 KT (same as <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002054#pcbi-1002054-g002\" target=\"_blank\">Fig. 2b</a>). The conformational selection and induced pathways from the unbound states to the encounter complex state is shown in green and grey arrows respectively.</p>", "links"=>[], "tags"=>["10", "highest", "flux", "pathways", "unbound", "states", "bound", "structures", "replaced", "plots", "twisting"], "article_id"=>441421, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Superposition_of_the_10_highest_flux_pathways_from_the_unbound_states_to_the_bound_state_as_in_Fig_2A_but_with_representative_structures_replaced_with_free_energy_plots_of_the_protein_opening_angle_versus_twisting_angle_/441421", "title"=>"Superposition of the 10 highest flux pathways from the unbound states to the bound state as in Fig. 2A but with representative structures replaced with free energy plots of the protein opening angle versus twisting angle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:23:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/771227"], "description"=>"<p>The X-ray apo (PDB ID: 2LAO) and bound structure (PDB ID: 1LAF) are shown in green and light blue respectively. Three representative conformations from the encounter complex state are superimposed and shown in red. These three conformations are representative of 10,000 randomly selected conformations from the encounter complex state (i.e. they have the smallest protein Cα RMSD to all the rest of the randomly selected conformations and are, therefore, the most central/typical of the state). In the right panel, the open, closed X-ray structures are overlaid with one of the representative conformations from the encounter complex state.</p>", "links"=>[], "tags"=>["comparisons", "x-ray", "apo", "bound", "structures", "lao"], "article_id"=>441594, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_comparisons_between_encounter_complex_and_X_ray_apo_or_open_and_bound_or_closed_structures_for_the_LAO_protein_/441594", "title"=>"Structural comparisons between encounter complex and X-ray apo (or open) and bound (or closed) structures for the LAO protein.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:26:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/771300"], "description"=>"<p>Green dots correspond to where transitions from the encounter complex to the bound state occur. Blue dots correspond to where transitions into the encounter complex from other states occur. Only transitions without re-crossing are counted (minimum residence time in the final state after the transition is 6 ns).</p>", "links"=>[], "tags"=>["plots", "twisting", "bound"], "article_id"=>441678, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overlay_of_free_energy_plots_of_the_protein_opening_angle_versus_twisting_angle_for_the_encounter_complex_red_and_bound_state_blue_/441678", "title"=>"Overlay of free energy plots of the protein opening angle versus twisting angle for the encounter complex (red) and bound state (blue).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:27:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/771385"], "description"=>"<p>The first step is the transition from the apo to the encounter complex state. In this step, multiple pathways exist where both conformational selection and the induced fit mechanisms play important roles. The second step is the transition from the encounter complex to the bound state, where the induced fit mechanism is adopted.</p>", "links"=>[], "tags"=>["schematic", "diagram", "describing", "two-step", "binding", "proteins", "steric", "occlusion"], "article_id"=>441749, "categories"=>["Physics", "Biochemistry"], "users"=>["Daniel-Adriano Silva", "Gregory R. Bowman", "Alejandro Sosa-Peinado", "Xuhui Huang"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002054.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_schematic_diagram_describing_the_proposed_two_step_binding_mechanism_for_proteins_in_steric_occlusion_of_the_direct_binding_of_the_ligands_/441749", "title"=>"A schematic diagram describing the proposed two-step binding mechanism for proteins in steric occlusion of the direct binding of the ligands.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-26 00:29:09"}

PMC Usage Stats | Further Information

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