{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T07:38:12Z","timestamp":1763105892870,"version":"build-2065373602"},"reference-count":87,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T00:00:00Z","timestamp":1659830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation Graduate Research Fellow-ship Program","doi-asserted-by":"publisher","award":["DGE-1939267","2137558"],"award-info":[{"award-number":["DGE-1939267","2137558"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-1939267","2137558"],"award-info":[{"award-number":["DGE-1939267","2137558"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The PDZ family has drawn attention as possible drug targets because of the domains\u2019 wide ranges of function and highly conserved binding pockets. The PICK1 PDZ domain has been proposed as a possible drug target because the interactions between the PICK1 PDZ domain and the GluA2 subunit of the AMPA receptor have been shown to progress neurodegenerative diseases. BIO124 has been identified as a sub \u00b5M inhibitor of the PICK1\u2013GluA2 interaction. Here, we use all-atom molecular dynamics simulations to reveal the atomic-level interaction pattern between the PICK1 PDZ domain and BIO124. Our simulations reveal three unique binding conformations of BIO124 in the PICK1 PDZ binding pocket, referred to here as state 0, state 1, and state 2. Each conformation is defined by a unique hydrogen bonding network and a unique pattern of hydrophobic interactions between BIO124 and the PICK1 PDZ domain. Interestingly, each conformation of BIO124 results in different dynamic changes to the PICK1 PDZ domain. Unlike states 1 and 2, state 0 induces dynamic coupling between BIO124 and the \u03b1A helix. Notably, this dynamic coupling with the \u03b1A helix is similar to what has been observed in other PDZ\u2013ligand complexes. Our analysis indicates that the interactions formed between BIO124 and I35 may be the key to inducing dynamic coupling with the \u03b1A helix. Lastly, we suspect that the conformational shifts observed in our simulations may affect the stability and thus the overall effectiveness of BIO124. We propose that a physically larger inhibitor may be necessary to ensure sufficient interactions that permit stable binding between a drug and the PICK1 PDZ domain.<\/jats:p>","DOI":"10.3390\/cells11152451","type":"journal-article","created":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T21:03:50Z","timestamp":1659906230000},"page":"2451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Three Binding Conformations of BIO124 in the Pocket of the PICK1 PDZ Domain"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9240-8393","authenticated-orcid":false,"given":"Amy O.","family":"Stevens","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Luo","sequence":"additional","affiliation":[{"name":"Albuquerque Academy, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-5312","authenticated-orcid":false,"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA"},{"name":"Translational Informatics Division, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0968-0004(00)89074-X","article-title":"Origin of PDZ (DHR, GLGF) domains","volume":"20","author":"Kennedy","year":"1995","journal-title":"Trends Biochem. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/pro.5560060225","article-title":"Evidence for PDZ domains in bacteria, yeast, and plants","volume":"6","author":"Ponting","year":"1997","journal-title":"Protein Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/382649a0","article-title":"Crystal structure of a PDZ domain","volume":"382","author":"Cabral","year":"1996","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1023\/A:1023941703493","article-title":"PDZ domains\u2014Glue and guide","volume":"30","author":"Hendriks","year":"2003","journal-title":"Mol. Biol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrn1517","article-title":"PDZ domain proteins of synapses","volume":"5","author":"Kim","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20130783","article-title":"Structures and target recognition modes of PDZ domains: Recurring themes and emerging pictures","volume":"455","author":"Ye","year":"2013","journal-title":"Biochem. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1016\/j.febslet.2012.03.056","article-title":"The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains","volume":"586","author":"Luck","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1242\/jcs.114.18.3219","article-title":"Mechanisma and role of PDZ domains in signaling complex assembly","volume":"114","author":"Harris","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/386284a0","article-title":"Homer: A protein that selectively binds metabotropic glutamate receptors","volume":"386","author":"Brakeman","year":"1997","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/B978-0-12-385952-5.00003-8","article-title":"Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs. Means, Motif, and Opportunity","volume":"62","author":"Romero","year":"2011","journal-title":"Adv. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tonikian, R., Zhang, Y., Sazinsky, S.L., Currell, B., Yeh, J.H., Reva, B., Held, H.A., Appleton, B.A., Evangelista, M., and Wu, Y. (2008). A Specificity Map for the PDZ Domain Family. PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060239"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0092-8674(00)81307-0","article-title":"Crystal structures of a complexed and peptide-free membrane protein- binding domain: Molecular basis of peptide recognition by PDZ","volume":"85","author":"Doyle","year":"1996","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/nrd1578","article-title":"Making protein interactions druggable: Targeting PDZ domains","volume":"3","author":"Dev","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1358\/dnp.2008.21.3.1203409","article-title":"Therapeutic use of PDZ protein-protein interaction antagonism","volume":"21","author":"Wang","year":"2008","journal-title":"Drug News Perspect."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/biof.1031","article-title":"Ligand binding by PDZ domains","volume":"38","author":"Chi","year":"2012","journal-title":"BioFactors"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1002\/cmdc.201100094","article-title":"Discovery, structure\u2013activity relationship studies, and crystal structure of nonpeptide inhibitors bound to the Shank3 PDZ domain","volume":"6","author":"Saupe","year":"2011","journal-title":"ChemMedChem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s11030-009-9187-z","article-title":"Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept","volume":"14","author":"Lisurek","year":"2010","journal-title":"Mol. Divers."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15495","DOI":"10.1021\/bi0512602","article-title":"Identification of a specific inhibitor of the Dishevelled PDZ domain","volume":"44","author":"Shan","year":"2005","journal-title":"Biochemistry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/j.1747-0285.2011.01295.x","article-title":"Synthesis of Potent Dishevelled PDZ Domain Inhibitors Guided by Virtual Screening and NMR Studies","volume":"79","author":"Shan","year":"2012","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1158\/0008-5472.CAN-06-2726","article-title":"An antagonist of dishevelled protein-protein interaction suppresses \u03b2-catenin\u2013dependent tumor cell growth","volume":"67","author":"Fujii","year":"2007","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.bmcl.2007.12.039","article-title":"Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity","volume":"18","author":"Mahindroo","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16256","DOI":"10.1074\/jbc.M109.009647","article-title":"Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled","volume":"284","author":"Grandy","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1016\/j.bmc.2016.03.026","article-title":"Identification of small-molecule compounds targeting the dishevelled PDZ domain by virtual screening and binding studies","volume":"24","author":"Choi","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s10822-018-0118-x","article-title":"Discovery of a small-molecule inhibitor of Dvl\u2013CXXC5 interaction by computational approaches","volume":"32","author":"Ma","year":"2018","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22299","DOI":"10.1074\/jbc.M602902200","article-title":"Convergent and Divergent Ligand Specificity among PDZ Domains of the LAP and Zonula Occludens (ZO) Families","volume":"281","author":"Zhang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1073\/pnas.1616100114","article-title":"Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9\/Syntenin","volume":"114","author":"Kegelman","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/1873-3468.12037","article-title":"Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of syntenin","volume":"590","author":"Garg","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e531","DOI":"10.1016\/j.ddtec.2012.10.003","article-title":"Inhibition of PDZ domain-mediated interactions","volume":"10","author":"Choquet","year":"2013","journal-title":"Drug Discov. Today Technol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lapchak, P.A., and Zhang, H.J. (2017). Neuroprotective Therapy for Stroke and Ischemic Disease, Springer.","DOI":"10.1007\/978-3-319-45345-3"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/aps.2018.5","article-title":"Discovery and development of NA-1 for the treatment of acute ischemic stroke","volume":"39","author":"Ballarin","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1073\/pnas.1113761109","article-title":"A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage","volume":"109","author":"Bach","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/pro.3361","article-title":"Lock and chop: A novel method for the generation of a PICK1 PDZ domain and piperidine-based inhibitor co-crystal structure","volume":"27","author":"Marcotte","year":"2018","journal-title":"Protein Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13438","DOI":"10.1038\/s41598-018-31680-3","article-title":"Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction","volume":"8","author":"Lin","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"590","DOI":"10.2174\/138620711796367201","article-title":"A Fluorescence Polarization Based Screening Assay for Identification of Small Molecule Inhibitors of the PICK1 PDZ Domain","volume":"14","author":"Thorsen","year":"2011","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S0896-6273(00)00160-4","article-title":"PDZ proteins interacting with C-terminal GluR2\/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses","volume":"28","author":"Daw","year":"2000","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.str.2015.04.020","article-title":"Structure of Dimeric and Tetrameric Complexes of the BAR Domain Protein PICK1 Determined by Small-Angle X-Ray Scattering","volume":"23","author":"Karlsen","year":"2015","journal-title":"Structure"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.pharmthera.2008.02.002","article-title":"PICK1: A multi-talented modulator of AMPA receptor trafficking","volume":"118","author":"Hanley","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12293","DOI":"10.1074\/jbc.M111.294702","article-title":"Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway","volume":"287","author":"Madsen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0028-3908(98)00230-5","article-title":"The protein kinase C\u03b1 binding protein PICK1 interacts with short but not long form alternative splice variants of AMPA receptor subunits","volume":"38","author":"Dev","year":"1999","journal-title":"Neuropharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.neuron.2005.07.006","article-title":"PICK1 interacts with ABP\/GRIP to regulate AMPA receptor trafficking","volume":"47","author":"Lu","year":"2005","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/ncb1688","article-title":"Inhibition of Arp2\/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis","volume":"10","author":"Rocca","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7024","DOI":"10.1523\/JNEUROSCI.1863-04.2004","article-title":"Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions","volume":"24","author":"Bjerggaard","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuint.2016.03.001","article-title":"Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases","volume":"98","author":"Li","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1073\/pnas.0902225107","article-title":"Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD","volume":"107","author":"Thorsen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1523\/JNEUROSCI.1221-08.2008","article-title":"Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking","volume":"28","author":"Famous","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107901","DOI":"10.1016\/j.neuropharm.2019.107901","article-title":"Administration of a novel high affinity PICK1 PDZ domain inhibitor attenuates cocaine seeking in rats","volume":"164","author":"Turner","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e11248","DOI":"10.15252\/emmm.201911248","article-title":"A high-affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain","volume":"12","author":"Christensen","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0896-6273(00)80689-3","article-title":"Clustering of AMPA receptors by the synaptic PD domain-containing protein PICK1","volume":"22","author":"Xia","year":"1999","journal-title":"Neuron"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1038\/sj.emboj.7600801","article-title":"PICK1 is a calcium-sensor for NMDA-induced AMPA receptor trafficking","volume":"24","author":"Hanley","year":"2005","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/156802607779318343","article-title":"PDZ domain protein-protein interactions: A case study with PICK1","volume":"7","author":"Dev","year":"2007","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"20195","DOI":"10.1074\/jbc.M113.471128","article-title":"Functional Modulation of the Glutamate Transporter Variant GLT1b by the PDZ Domain Protein PICK1","volume":"288","author":"Sogaard","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1111\/ejn.12499","article-title":"Synapto-depressive effects of amyloid beta require PICK1","volume":"39","author":"Alfonso","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E5825","DOI":"10.1073\/pnas.1705311114","article-title":"Hidden electrostatic basis of dynamic allostery in a PDZ domain","volume":"114","author":"Kumawat","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8931","DOI":"10.1021\/ja0752080","article-title":"Mapping of two networks of residues that exhibit structural and dynamical changes upon binding in a PDZ domain protein","volume":"130","author":"Dhulesia","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5677","DOI":"10.1021\/ct500326g","article-title":"Mechanisms of differential allosteric modulation in homologous proteins: Insights from the analysis of internal dynamics and energetics of PDZ domains","volume":"10","author":"Morra","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/prot.22139","article-title":"Signaling pathways of PDZ2 domain: A molecular dynamics interaction correlation analysis","volume":"74","author":"Kong","year":"2009","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1021\/jp5083455","article-title":"Identifying key residues for protein allostery through rigid residue scan","volume":"119","author":"Kalescky","year":"2015","journal-title":"J. Phys. Chem. A"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM Simulations using the CHARMM36 Additive Force Field","volume":"12","author":"Lee","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: An improved force field for folded and intrinsically disordered proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-15976-8_1","article-title":"Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS","volume":"Volume 8759","author":"Markidis","year":"2015","journal-title":"Solving Software Challenges for Exascale: International Conference on Exascale Applications and Software, EASC 2014, Stockholm, Sweden, 2\u20133 April 2014, Revised Selected Papers"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1063\/1.447334","article-title":"A unified formulation of the constant temperature molecular dynamics methods","volume":"81","author":"Nose","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical dynamics: Equilibrium phase-space distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"McCammon, J.A., and Harvey, S.C. (1987). Dynamics of Proteins and Nucleic Acids, Cambridge University Press.","DOI":"10.1017\/CBO9781139167864"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"026113","DOI":"10.1103\/PhysRevE.69.026113","article-title":"Finding and evaluating community structure in networks","volume":"69","author":"Newman","year":"2004","journal-title":"Phys. Rev. E-Stat. Nonlinear Soft Matter Phys."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/bioinformatics\/btl461","article-title":"Bio3d: An R package for the comparative analysis of protein structures","volume":"22","author":"Grant","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Skjaerven, L., Yao, X.Q., Scarabelli, G., and Grant, B.J. (2014). Integrating protein structural dynamics and evolutionary analysis with Bio3D. BMC Bioinform., 15.","DOI":"10.1186\/s12859-014-0399-6"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/pro.3923","article-title":"The Bio3D packages for structural bioinformatics","volume":"30","author":"Grant","year":"2021","journal-title":"Protein Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Costescu, B.I., and Gr\u00e4ter, F. (2013). Time-resolved force distribution analysis. BMC Biophys., 6.","DOI":"10.1186\/2046-1682-6-5"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1038\/sj.emboj.7601860","article-title":"Clustering and synaptic targeting of PICK1 requires direct interaction between the PDZ domain and lipid membranes","volume":"26","author":"Pan","year":"2007","journal-title":"EMBO J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Stevens, A.O., and He, Y. (2022). Allosterism in the PDZ Family. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031454"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/nature11500","article-title":"The spatial architecture of protein function and adaptation","volume":"491","author":"Poelwijk","year":"2012","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1006\/jmbi.2002.5402","article-title":"Structure, dynamics and binding characteristics of the second PDZ domain of PTP-BL","volume":"316","author":"Walma","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.jmb.2005.05.043","article-title":"Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion","volume":"351","author":"Ota","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_78","first-page":"345","article-title":"Evaluation of Energetic and Dynamic Coupling Networks in a PDZ Domain Protein","volume":"351","author":"Fuentes","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/pro.318","article-title":"Conserved tertiary couplings stabilize elements in the PDZ fold, leading to characteristic patterns of domain conformational flexibility","volume":"19","author":"Ho","year":"2010","journal-title":"Protein Sci."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Du, Q.-S., Wang, C.-H., Liao, S.-M., and Huang, R.-B. (2010). Correlation Analysis for Protein Evolutionary Family Based on Amino Acid Position Mutations and Application in PDZ Domain. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013207"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Gerek, Z.N., and Ozkan, S.B. (2011). Change in allosteric network affects binding affinities of PDZ domains: Analysis through perturbation response scanning. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002154"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Cilia, E., Vuister, G.W., and Lenaerts, T. (2012). Accurate Prediction of the Dynamical Changes within the Second PDZ Domain of PTP1e. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002794"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1126\/science.286.5438.295","article-title":"Evolutionarily conserved pathways of energetic connectivity in protein families","volume":"286","author":"Lockless","year":"1999","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.str.2006.10.010","article-title":"Demonstration of Long-Range Interactions in a PDZ Domain by NMR, Kinetics, and Protein Engineering","volume":"14","author":"Gianni","year":"2006","journal-title":"Structure"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"25327","DOI":"10.1074\/jbc.M114.548743","article-title":"Protein interacting with C-kinase 1 (PICK1) binding promiscuity relies on unconventional PSD-95\/discs-large\/ZO-1 homology (PDZ) binding modes for nonclass II PDZ ligands","volume":"289","author":"Erlendsson","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.jmb.2003.11.010","article-title":"Ligand-dependent Dynamics and Intramolecular Signaling in a PDZ Domain","volume":"335","author":"Fuentes","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1021\/ct400096f","article-title":"A mixed protein structure network and elastic network model approach to predict the structural communication in biomolecular systems: The PDZ2 domain from tyrosine phosphatase 1E as a case study","volume":"9","author":"Raimondi","year":"2013","journal-title":"J. Chem. Theory Comput."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/15\/2451\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:05:27Z","timestamp":1760141127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/15\/2451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,7]]},"references-count":87,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cells11152451"],"URL":"https:\/\/doi.org\/10.3390\/cells11152451","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2022,8,7]]}}}