{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:56:18Z","timestamp":1778777778287,"version":"3.51.4"},"reference-count":124,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2016,7,13]],"date-time":"2016-07-13T00:00:00Z","timestamp":1468368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FIRB","award":["RBFR12SJA8_003"],"award-info":[{"award-number":["RBFR12SJA8_003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Among the different aquaporins (AQPs), human aquaporin-4 (hAQP4) has attracted the greatest interest in recent years as a new promising therapeutic target. Such a membrane protein is, in fact, involved in a multiple sclerosis-like immunopathology called Neuromyelitis Optica (NMO) and in several disorders resulting from imbalanced water homeostasis such as deafness and cerebral edema. The gap of knowledge in its functioning and dynamics at the atomistic level of detail has hindered the development of rational strategies for designing hAQP4 modulators. The application, lately, of molecular modeling has proved able to fill this gap providing a breeding ground to rationally address compounds targeting hAQP4. In this review, we give an overview of the important advances obtained in this field through the application of Molecular Dynamics (MD) and other complementary modeling techniques. The case studies presented herein are discussed with the aim of providing important clues for computational chemists and biophysicists interested in this field and looking for new challenges.<\/jats:p>","DOI":"10.3390\/ijms17071119","type":"journal-article","created":{"date-parts":[[2016,7,13]],"date-time":"2016-07-13T09:48:45Z","timestamp":1468403325000},"page":"1119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Human Aquaporin-4 and Molecular Modeling: Historical Perspective and View to the Future"],"prefix":"10.3390","volume":"17","author":[{"given":"Giuseppe","family":"Mangiatordi","sequence":"first","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, University of Bari \u201dAldo Moro\u201d, 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Alberga","sequence":"additional","affiliation":[{"name":"Institut de Recherche de Chimie Paris CNRS Chimie ParisTech, PSL Research University, 11 rue P. et M. Curie, F-75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Trisciuzzi","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, University of Bari \u201dAldo Moro\u201d, 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-6457","authenticated-orcid":false,"given":"Gianluca","family":"Lattanzi","sequence":"additional","affiliation":[{"name":"INFN-Sez. di Bari and Dipartimento di Medicina Clinica e Sperimentale, University of Foggia, Viale Pinto, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9475-9602","authenticated-orcid":false,"given":"Orazio","family":"Nicolotti","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, University of Bari \u201dAldo Moro\u201d, 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1523\/JNEUROSCI.17-01-00171.1997","article-title":"Specialized membrane domains for water transport in glial cells: High-resolution immunogold cytochemistry of aquaporin-4 in rat brain","volume":"17","author":"Nielsen","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.biochem.68.1.425","article-title":"Cellular and molecular biology of the aquaporin water channels","volume":"68","author":"Borgnia","year":"1999","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/414872a","article-title":"Structural basis of water-specific transport through the AQP1 water channel","volume":"414","author":"Sui","year":"2001","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.pbiomolbio.2014.01.002","article-title":"Insights into structural mechanisms of gating induced regulation of aquaporins","volume":"114","author":"Sachdeva","year":"2014","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/prot.20038","article-title":"The mechanism of proton exclusion in aquaporin channels","volume":"55","author":"Ilan","year":"2004","journal-title":"Proteins"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jmb.2011.01.036","article-title":"Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1","volume":"407","author":"Li","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1073\/pnas.0707662104","article-title":"Mechanism of selectivity in aquaporins and aquaglyceroporins","volume":"105","author":"Hub","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7436","DOI":"10.1021\/bi00148a002","article-title":"Reconstitution of functional water channels in liposomes containing purified red cell CHIP28 protein","volume":"31","author":"Zeidel","year":"1992","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1113\/jphysiol.2002.020818","article-title":"Aquaporin water channels\u2014From atomic structure to clinical medicine","volume":"542","author":"Agre","year":"2002","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1016\/j.bbagen.2013.09.033","article-title":"Human aquaporins: Regulators of transcellular water flow","volume":"1840","author":"Day","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1358\/dnp.2007.20.7.1138161","article-title":"Aquaporin-related disorders of water homeostasis","volume":"20","author":"Schrier","year":"2007","journal-title":"Drug News Perspect."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0014-5793(03)01083-4","article-title":"Aquaporin water channels: Molecular mechanisms for human diseases 1","volume":"555","author":"Agre","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.20050304","article-title":"IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel","volume":"202","author":"Lennon","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S1359-6446(05)03390-8","article-title":"Aquaporins as targets for drug discovery","volume":"10","author":"Castle","year":"2005","journal-title":"Drug Discov. Today"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jmb.2003.08.003","article-title":"The mechanism of proton exclusion in the aquaporin-1 water channel","volume":"333","author":"Frigato","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-3-540-79885-9_3","article-title":"Dynamics and energetics of permeation through aquaporins. What do we learn from molecular dynamics simulations?","volume":"190","author":"Hub","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L97","DOI":"10.1016\/j.bpj.2010.11.003","article-title":"Voltage-regulated water flux through aquaporin channels in silico","volume":"99","author":"Hub","year":"2010","journal-title":"Biophys. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9887","DOI":"10.1073\/pnas.1121054109","article-title":"Molecular driving forces defining lipid positions around aquaporin-0","volume":"109","author":"Briones","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1021\/cb300153z","article-title":"Discovery of novel human aquaporin-1 blockers","volume":"8","author":"Seeliger","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/glia.22498","article-title":"Phosphorylation of rat aquaporin-4 at Ser111 is not required for channel gating","volume":"61","author":"Assentoft","year":"2013","journal-title":"Glia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7437","DOI":"10.1073\/pnas.0902725106","article-title":"Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance","volume":"106","author":"Ho","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1016\/j.bbamem.2014.08.015","article-title":"A new gating site in human aquaporin-4: Insights from molecular dynamics simulations","volume":"1838","author":"Alberga","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1006\/geno.1998.5337","article-title":"Isolation and functional analysis of alternative promoters in the human aquaporin-4 water channel gene","volume":"50","author":"Umenishi","year":"1998","journal-title":"Genomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"22907","DOI":"10.1074\/jbc.270.39.22907","article-title":"cDNA cloning, gene organization, and chromosomal localization of a human mercurial insensitive water channel","volume":"270","author":"Yang","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/nrn1252","article-title":"The molecular basis of water transport in the brain","volume":"4","author":"Ottersen","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0169-328X(01)00067-5","article-title":"Regulation of aquaporin-4 expression in astrocytes","volume":"89","author":"Yoneda","year":"2001","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neuroscience.2011.09.023","article-title":"D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness","volume":"197","author":"Nicchia","year":"2011","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"31233","DOI":"10.1074\/jbc.M104368200","article-title":"Impaired hearing in mice lacking aquaporin-4 water channels","volume":"276","author":"Li","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/978-3-540-79885-9_7","article-title":"Role of aquaporin-4 in cerebral edema and stroke","volume":"190","author":"Zador","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1007\/s00467-006-0411-0","article-title":"Aquaporin-4 and brain edema","volume":"22","author":"Papadopoulos","year":"2007","journal-title":"Pediatr. Nephrol. Berl. Ger."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.eplepsyres.2009.09.023","article-title":"Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy","volume":"88","author":"Heuser","year":"2010","journal-title":"Epilepsy Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bbadis.2003.09.005","article-title":"Administration of the soluble complement inhibitor, Crry-Ig, reduces inflammation and aquaporin 4 expression in lupus cerebritis","volume":"1639","author":"Alexander","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1007\/s00330-009-1425-3","article-title":"Spinal cord lesions in patients with neuromyelitis optica: a retrospective long-term MRI follow-up study","volume":"19","author":"Krampla","year":"2009","journal-title":"Eur. Radiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.bmcl.2006.12.010","article-title":"Identification of arylsulfonamides as Aquaporin 4 inhibitors","volume":"17","author":"Huber","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jsb.2008.11.010","article-title":"Acetazolamide reversibly inhibits water conduction by aquaporin-4","volume":"166","author":"Tanimura","year":"2009","journal-title":"J. Struct. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10072-010-0431-1","article-title":"Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema","volume":"32","author":"Igarashi","year":"2011","journal-title":"Neurol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.bmc.2007.12.040","article-title":"Identification of aquaporin 4 inhibitors using in vitro and in silico methods","volume":"17","author":"Huber","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1096\/fj.11-201608","article-title":"Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica","volume":"26","author":"Tradtrantip","year":"2012","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrneurol.2014.141","article-title":"Treatment of neuromyelitis optica: State-of-the-art and emerging therapies","volume":"10","author":"Papadopoulos","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-540-79885-9_1","article-title":"Discovery of the aquaporins and development of the field","volume":"Volume 190","author":"Beitz","year":"2009","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_41","first-page":"F13","article-title":"Structure and function of aquaporin water channels","volume":"278","author":"Verkman","year":"2000","journal-title":"Am. J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/0009-2614(95)00905-J","article-title":"The Grotthuss mechanism","volume":"244","author":"Agmon","year":"1995","journal-title":"Chem. Phys. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0014-5793(01)02743-0","article-title":"A refined structure of human aquaporin-1","volume":"504","author":"Engel","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1126\/science.1066115","article-title":"Water permeation across biological membranes: Mechanism and dynamics of aquaporin-1 and GlpF","volume":"294","year":"2001","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.1067778","article-title":"Control of the selectivity of the aquaporin water channel family by global orientational tuning","volume":"296","author":"Tajkhorshid","year":"2002","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.jmb.2004.08.036","article-title":"Structural determinants of proton blockage in aquaporins","volume":"343","author":"Chakrabarti","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"L73","DOI":"10.1529\/biophysj.106.084061","article-title":"Origins of proton transport behavior from selectivity domain mutations of the aquaporin-1 channel","volume":"90","author":"Chen","year":"2006","journal-title":"Biophys. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.sbi.2015.08.004","article-title":"Structural insights into aquaporin selectivity and regulation","volume":"33","author":"Kreida","year":"2015","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1126\/science.1234306","article-title":"Subangstrom resolution X-ray structure details aquaporin-water interactions","volume":"340","author":"Fischer","year":"2013","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1073\/pnas.0507225103","article-title":"Point mutations in the aromatic\/arginine region in aquaporin 1 allow passage of urea, glycerol, ammonia, and protons","volume":"103","author":"Beitz","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1016\/S0006-3495(93)81293-1","article-title":"The pore dimensions of gramicidin A","volume":"65","author":"Smart","year":"1993","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.bbrc.2011.08.019","article-title":"Water transport in human aquaporin-4: Molecular dynamics (MD) simulations","volume":"412","author":"Cui","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Deuflhard, P., Hermans, J., Leimkuhler, B., Mark, A.E., Reich, S., and Skeel, R.D. (1999). Computational Molecular Dynamics: Challenges, Methods, Ideas, Springer.","DOI":"10.1007\/978-3-642-58360-5"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/00268978200100161","article-title":"Brownian dynamics and the fluctuation-dissipation theorem","volume":"45","author":"Bossis","year":"1982","journal-title":"Mol. Phys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.bpj.2011.06.010","article-title":"Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail","volume":"101","author":"Kutzner","year":"2011","journal-title":"Biophys. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1085\/jgp.200308990","article-title":"Molecular basis of pH and Ca2+ regulation of aquaporin water permeability","volume":"123","author":"Kalman","year":"2004","journal-title":"J. Gen. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30037","DOI":"10.1074\/jbc.M302206200","article-title":"Nickel and extracellular acidification inhibit the water permeability of human aquaporin-3 in lung epithelial cells","volume":"278","author":"Zelenina","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"51939","DOI":"10.1074\/jbc.M407645200","article-title":"Copper inhibits the water and glycerol permeability of aquaporin-3","volume":"279","author":"Zelenina","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6337","DOI":"10.1074\/jbc.M209792200","article-title":"A short regulatory domain restricts glycerol transport through yeast Fps1p","volume":"278","author":"Karlgren","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_60","first-page":"1181","article-title":"The major integral proteins of spinach leaf plasma membranes are putative aquaporins and are phosphorylated in response to Ca2+ and apoplastic water potential","volume":"8","author":"Johansson","year":"1996","journal-title":"Plant. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nature01853","article-title":"Cytosolic pH regulates root water transport during anoxic stress through gating of aquaporins","volume":"425","author":"Sutka","year":"2003","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"F309","DOI":"10.1152\/ajprenal.00260.2001","article-title":"Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine","volume":"283","author":"Zelenina","year":"2002","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/glia.20627","article-title":"Identification of a molecular target for glutamate regulation of astrocyte water permeability","volume":"56","author":"Gunnarson","year":"2008","journal-title":"Glia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6753","DOI":"10.1021\/acs.biochem.5b01053","article-title":"Control of the aquaporin-4 channel water permeability by structural dynamics of aromatic\/arginine selectivity filter residues","volume":"54","author":"Kitchen","year":"2015","journal-title":"Biochemistry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/j.str.2006.07.006","article-title":"Mechanism of gating and ion conductivity of a possible tetrameric pore in aquaporin-1","volume":"14","author":"Yu","year":"2006","journal-title":"Structure"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.jmb.2009.01.065","article-title":"Structural and Functional Analysis of SoPIP2;1 Mutants Adds Insight into Plant Aquaporin Gating","volume":"387","author":"Nyblom","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Janosi, L., and Ceccarelli, M. (2013). The gating mechanism of the human aquaporin 5 revealed by molecular dynamics simulations. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059897"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1529\/biophysj.106.101170","article-title":"Water transport in aquaporins: Osmotic permeability matrix analysis of molecular dynamics simulations","volume":"93","author":"Hashido","year":"2007","journal-title":"Biophys. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1021\/ci700119r","article-title":"Screening of matrix metalloproteinases available from the protein data bank: Insights into biological functions, domain organization, and zinc binding groups","volume":"47","author":"Nicolotti","year":"2007","journal-title":"J. Chem. Inf. Model."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6313","DOI":"10.1074\/jbc.M010326200","article-title":"A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2","volume":"276","author":"Zong","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1152\/physrev.00016.2014","article-title":"Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels","volume":"95","author":"Teulon","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6900","DOI":"10.1073\/pnas.0800873105","article-title":"Molecular mechanism of pH sensing in KcsA potassium channels","volume":"105","author":"Thompson","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1016\/j.str.2015.08.020","article-title":"H95 is a pH-dependent gate in aquaporin 4","volume":"23","author":"Kaptan","year":"2015","journal-title":"Structures"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.bpj.2012.07.022","article-title":"Partial least-squares functional mode analysis: Application to the membrane proteins AQP1, Aqy1, and CLC-ec1","volume":"103","author":"Krivobokova","year":"2012","journal-title":"Biophys. J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/nature06522","article-title":"Dynamic personalities of proteins","volume":"450","author":"Kern","year":"2007","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1042\/BJ20121221","article-title":"Residue mutations and their impact on protein structure and function: detecting beneficial and pathogenic changes","volume":"449","author":"Studer","year":"2013","journal-title":"Biochem. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ajhg.2011.06.008","article-title":"A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease","volume":"89","author":"Zimprich","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1093-3263(01)00117-6","article-title":"Flexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations","volume":"20","author":"Gsponer","year":"2001","journal-title":"J. Mol. Graph. Model."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/prot.20401","article-title":"One gene, two diseases and three conformations: Molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures","volume":"59","author":"Shamsir","year":"2005","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_80","first-page":"37","article-title":"Screening of mutations affecting protein stability and dynamics of FGFR1\u2014A simulation analysis","volume":"1","author":"Doss","year":"2012","journal-title":"Appl. Transl. Genom."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0006-3495(01)75791-8","article-title":"Molecular dynamics simulations of wild-type and mutant forms of the Mycobacterium tuberculosis MscL channel","volume":"81","author":"Elmore","year":"2001","journal-title":"Biophys. J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3390\/ijms12010128","article-title":"Insight into a novel p53 single point mutation (G389E) by molecular dynamics simulations","volume":"12","author":"Pirolli","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1113\/JP270358","article-title":"ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype\u2013phenotype correlation","volume":"593","author":"Imbrici","year":"2015","journal-title":"J. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"23748","DOI":"10.1074\/jbc.272.38.23748","article-title":"Molecular modeling-guided mutagenesis of the extracellular part of gp130 leads to the identification of contact sites in the interleukin-6 (IL-6)\u00b7IL-6 receptor\u00b7gp130 Complex","volume":"272","author":"Horsten","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2174\/138920007779315062","article-title":"Molecular modeling-guided site-directed mutagenesis of cytochrome P450 2D6","volume":"8","author":"Oostenbrink","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.jmb.2009.12.055","article-title":"Model-guided mutagenesis drives functional studies of human NHA2, implicated in hypertension","volume":"396","author":"Schushan","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1074\/jbc.272.6.3657","article-title":"Prostacyclin synthase active sites identification by molecular modeling-guided site-directed mutagenesis","volume":"272","author":"Shyue","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"19970","DOI":"10.1074\/jbc.271.33.19970","article-title":"Identification of thromboxane A2 synthase active site residues by molecular modeling-guided site-directed mutagenesis","volume":"271","author":"Wang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1093\/brain\/awf151","article-title":"A role for humoral mechanisms in the pathogenesis of Devic\u2019s neuromyelitis optica","volume":"125","author":"Lucchinetti","year":"2002","journal-title":"Brain"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jns.2011.08.043","article-title":"Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis: Astrocytopathy as a common denominator in demyelinating disorders","volume":"311","author":"Kira","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1474-4422(12)70133-3","article-title":"Aquaporin 4 and neuromyelitis optica","volume":"11","author":"Papadopoulos","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"9216","DOI":"10.1074\/jbc.M110.123000","article-title":"Identification of two major conformational aquaporin-4 epitopes for neuromyelitis optica autoantibody binding","volume":"286","author":"Pisani","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1600-0854.2011.01299.x","article-title":"Post-golgi supramolecular assembly of aquaporin-4 in orthogonal arrays","volume":"13","author":"Rossi","year":"2012","journal-title":"Traffic"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1002\/glia.20855","article-title":"Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies","volume":"57","author":"Nicchia","year":"2009","journal-title":"Glia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"30578","DOI":"10.1074\/jbc.M114.582221","article-title":"Identification of a point mutation impairing the binding between aquaporin-4 and neuromyelitis optica autoantibodies","volume":"289","author":"Pisani","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1016\/j.bbamem.2015.03.019","article-title":"Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields","volume":"1848","author":"Mangiatordi","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1574-1400(09)00502-7","article-title":"Quantifying uncertainty and sampling quality in biomolecular simulations","volume":"5","author":"Grossfield","year":"2009","journal-title":"Annu. Rep. Comput. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.cbpa.2006.06.014","article-title":"A practical view of \u2032druggability\u2032","volume":"10","author":"Keller","year":"2006","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrd4226","article-title":"Aquaporins: Important but elusive drug targets","volume":"13","author":"Verkman","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1476-5381.2010.01127.x","article-title":"Principles of early drug discovery","volume":"162","author":"Hughes","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1021\/jm100574m","article-title":"Understanding and predicting druggability. A high-throughput method for detection of drug binding sites","volume":"53","author":"Schmidtke","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Hussein, H.A., Borrel, A., Geneix, C., Petitjean, M., Regad, L., and Camproux, A.-C. (2015). PockDrug-Server: A new web server for predicting pocket druggability on holo and apo proteins. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkv462"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.drudis.2011.02.002","article-title":"Fragment screening to predict druggability (ligandability) and lead discovery success","volume":"16","author":"Edfeldt","year":"2011","journal-title":"Drug Discov. Today"},{"key":"ref_104","first-page":"366","article-title":"Prediction of druggable proteins using machine learning and systems biology: A mini-review","volume":"6","author":"Kandoi","year":"2015","journal-title":"Syst. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"9063","DOI":"10.1021\/acs.jmedchem.5b00586","article-title":"New frontiers in druggability","volume":"58","author":"Kozakov","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/S0928-0987(00)00162-7","article-title":"VolSurf: A new tool for the pharmacokinetic optimization of lead compounds","volume":"11","author":"Cruciani","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/jmr.984","article-title":"Computational approaches to identifying and characterizing protein binding sites for ligand design","volume":"23","author":"Henrich","year":"2010","journal-title":"J. Mol. Recognit."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s10822-012-9612-8","article-title":"Ligand-, structure- and pharmacophore-based molecular fingerprints: A case study on adenosine A1, A2A, A2B, and A3 receptor antagonists","volume":"26","author":"Sirci","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1021\/jm00145a002","article-title":"A computational procedure for determining energetically favorable binding sites on biologically important macromolecules","volume":"28","author":"Goodford","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nbt1273","article-title":"Structure-based maximal affinity model predicts small-molecule druggability","volume":"25","author":"Cheng","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-386043-9.00001-3","article-title":"Structure and functions of aquaporin-4-based orthogonal arrays of particles","volume":"287","author":"Wolburg","year":"2011","journal-title":"Int. Rev. Cell. Mol. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1016\/j.bpj.2009.09.017","article-title":"Reversible, temperature-dependent supramolecular assembly of aquaporin-4 orthogonal arrays in live cell membranes","volume":"97","author":"Crane","year":"2009","journal-title":"Biophys. J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"13749","DOI":"10.1073\/pnas.0506346102","article-title":"Replica exchange with solute tempering: A method for sampling biological systems in explicit water","volume":"102","author":"Liu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nature03197","article-title":"Virtual screening of chemical libraries","volume":"432","author":"Shoichet","year":"2004","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nrd1549","article-title":"Docking and scoring in virtual screening for drug discovery: Methods and applications","volume":"3","author":"Kitchen","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.drudis.2011.02.011","article-title":"State-of-the-art in ligand-based virtual screening","volume":"16","author":"Ripphausen","year":"2011","journal-title":"Drug Discov. Today"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.cbpa.2006.04.002","article-title":"Structure-based virtual screening of chemical libraries for drug discovery","volume":"10","author":"Ghosh","year":"2006","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Loving, K.A., Lin, A., and Cheng, A.C. (2014). Structure-based druggability assessment of the mammalian structural proteome with inclusion of light protein flexibility. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003741"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1021\/ci800081s","article-title":"Fully automated molecular mechanics based induced fit protein-ligand docking method","volume":"48","author":"Koska","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1021\/ci4004927","article-title":"BP-Dock: A flexible docking scheme for exploring protein-ligand interactions based on unbound structures","volume":"54","author":"Bolia","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ddstr.2011.10.002","article-title":"Drug repurposing from an academic perspective","volume":"8","author":"Oprea","year":"2011","journal-title":"Drug Discov. Today Ther. Strateg."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"197","DOI":"10.47276\/lr.78.3.197","article-title":"The role of thalidomide in the management of erythema nodosum leprosum","volume":"78","author":"Walker","year":"2007","journal-title":"Lepr. Rev."},{"key":"ref_123","first-page":"47","article-title":"Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction","volume":"8","author":"Boolell","year":"1996","journal-title":"Int. J. Impot. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1358\/dnp.2009.22.2.1343228","article-title":"The value of drug repositioning in the current pharmaceutical market","volume":"22","author":"Tobinick","year":"2009","journal-title":"Drug News Perspect."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/7\/1119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:26:03Z","timestamp":1760210763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/7\/1119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,13]]},"references-count":124,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2016,7]]}},"alternative-id":["ijms17071119"],"URL":"https:\/\/doi.org\/10.3390\/ijms17071119","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,13]]}}}