{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T22:00:41Z","timestamp":1774648841253,"version":"3.50.1"},"reference-count":122,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Bada\u0144 i Rozwoju","doi-asserted-by":"publisher","award":["STRATEGMED1\/235077\/9\/NCBR\/2014"],"award-info":[{"award-number":["STRATEGMED1\/235077\/9\/NCBR\/2014"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2015\/19\/B\/NZ4\/03571NCN"],"award-info":[{"award-number":["2015\/19\/B\/NZ4\/03571NCN"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemic stroke is a disturbance in cerebral blood flow caused by brain tissue ischemia and hypoxia. We optimized a multifactorial in vitro model of acute ischemic stroke using rat primary neural cultures. This model was exploited to investigate the pro-viable activity of cell-penetrating peptides: arginine-rich Tat(49\u201357)-NH2 (R49KKRRQRRR57-amide) and its less basic analogue, PTD4 (Y47ARAAARQARA57-amide). Our model included glucose deprivation, oxidative stress, lactic acidosis, and excitotoxicity. Neurotoxicity of these peptides was excluded below a concentration of 50 \u03bcm, and PTD4-induced pro-survival was more pronounced. Circular dichroism spectroscopy and molecular dynamics (MD) calculations proved potential contribution of the peptide conformational properties to neuroprotection: in MD, Tat(49\u201357)-NH2 adopted a random coil and polyproline type II helical structure, whereas PTD4 adopted a helical structure. In an aqueous environment, the peptides mostly adopted a random coil conformation (PTD4) or a polyproline type II helical (Tat(49\u201357)-NH2) structure. In 30% TFE, PTD4 showed a tendency to adopt a helical structure. Overall, the pro-viable activity of PTD4 was not correlated with the arginine content but rather with the peptide\u2019s ability to adopt a helical structure in the membrane-mimicking environment, which enhances its cell membrane permeability. PTD4 may act as a leader sequence in novel drugs for the treatment of acute ischemic stroke.<\/jats:p>","DOI":"10.3390\/ijms22116086","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T11:12:13Z","timestamp":1622805133000},"page":"6086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PTD4 Peptide Increases Neural Viability in an In Vitro Model of Acute Ischemic Stroke"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-7136","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Mazuryk","sequence":"first","affiliation":[{"name":"Laboratory of Neurobiology, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland"},{"name":"Department of Electrode Processes, Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44\/52, 01-224 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1419-4200","authenticated-orcid":false,"given":"Izabela","family":"Puchalska","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"},{"name":"Institute of Biotechnology and Molecular Medicine, 80-172 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-687X","authenticated-orcid":false,"given":"Kamil","family":"Kozi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-4679","authenticated-orcid":false,"given":"Magdalena J.","family":"\u015alusarz","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1945-194X","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Ruczy\u0144ski","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-4833","authenticated-orcid":false,"given":"Piotr","family":"Rekowski","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2815-4055","authenticated-orcid":false,"given":"Piotr","family":"Rogujski","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland"},{"name":"NeuroRepair Department, Mossakowski Medical Research Institute PAS, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8850-8674","authenticated-orcid":false,"given":"Rafa\u0142","family":"P\u0142atek","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland"},{"name":"Laboratory for Regenerative Biotechnology, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1593-0361","authenticated-orcid":false,"given":"Marta Barbara","family":"Wi\u015bniewska","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0823-0607","authenticated-orcid":false,"given":"Arkadiusz","family":"Piotrowski","sequence":"additional","affiliation":[{"name":"Department of Biology and Pharmaceutical Botany, Faculty of Pharmacy, Medical University of Gda\u0144sk, 80-416 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u0141ukasz","family":"Janus","sequence":"additional","affiliation":[{"name":"MedVentures Company, 60-141 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1345-3271","authenticated-orcid":false,"given":"Piotr M.","family":"Skowron","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7751-9781","authenticated-orcid":false,"given":"Micha\u0142","family":"Piku\u0142a","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Engineering and Regenerative Medicine, Department of Embryology, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5087-844X","authenticated-orcid":false,"given":"Pawe\u0142","family":"Sachadyn","sequence":"additional","affiliation":[{"name":"Laboratory for Regenerative Biotechnology, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4471-5951","authenticated-orcid":false,"given":"Sylwia","family":"Rodziewicz-Motowid\u0142o","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-2114","authenticated-orcid":false,"given":"Artur","family":"Czupryn","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0269-8620","authenticated-orcid":false,"given":"Piotr","family":"Mucha","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0140-6736(13)61953-4","article-title":"Global and regional burden of stroke during 1990\u20132010: Findings from the Global Burden of Disease Study 2010","volume":"383","author":"Feigin","year":"2014","journal-title":"Lancet"},{"key":"ref_2","first-page":"e38","article-title":"Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association","volume":"133","author":"Mozaffarian","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1177\/2396987319883160","article-title":"Economic burden of stroke across Europe: A population-based cost analysis","volume":"5","author":"Violato","year":"2020","journal-title":"Eur. Stroke J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1385\/MN:31:1-3:003","article-title":"Kainic acid-mediated excitotoxicity as a model for neurodegeneration","volume":"31","author":"Wang","year":"2005","journal-title":"Mol. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/jcbfm.2015.11","article-title":"Poly-arginine and arginine-rich peptides are neuroprotective in stroke models","volume":"35","author":"Meloni","year":"2015","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995). Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med., 333, 1581\u20131587.","DOI":"10.1056\/NEJM199512143332401"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e676","DOI":"10.3928\/01477447-20130426-35","article-title":"Reversal of acute ischemic stroke after THA using tissue plasminogen activator","volume":"36","author":"Ezzet","year":"2013","journal-title":"Orthopedics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1080\/17425247.2019.1676720","article-title":"Cell penetrating peptides: The potent multi-cargo intracellular carriers","volume":"16","author":"Kardani","year":"2019","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1021\/acs.bioconjchem.8b00894","article-title":"TP10-Dopamine Conjugate as a Potential Therapeutic Agent in the Treatment of Parkinson\u2019s Disease","volume":"30","author":"Rusiecka","year":"2019","journal-title":"Bioconjug. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16883","DOI":"10.1073\/pnas.1108795108","article-title":"Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions","volume":"108","author":"Mishra","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.febslet.2009.11.046","article-title":"Arginine-rich cell-penetrating peptides","volume":"584","author":"Schmidt","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1021\/bi0206199","article-title":"Inhibition of nuclear import mediated by the Rev-arginine rich motif by RNA molecules","volume":"42","author":"Fineberg","year":"2003","journal-title":"Biochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.1039\/C6CS00076B","article-title":"Blood-brain barrier shuttle peptides: An emerging paradigm for brain delivery","volume":"45","author":"Giralt","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_14","first-page":"41","article-title":"Protein transduction domain peptide mediates delivery to the brain via the blood-brain barrier in Drosophila","volume":"55","author":"Sarantseva","year":"2009","journal-title":"Biomeditsinskaia Khimiia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3389\/fmicb.2017.00080","article-title":"HIV-1 Tat and Viral Latency: What We Can Learn from Naturally Occurring Sequence Variations","volume":"8","author":"Kamori","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.pharmthera.2015.06.002","article-title":"Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties","volume":"153","author":"Meloni","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1006\/jmbi.1997.1347","article-title":"Role of beta-turn residues in beta-hairpin formation and stability in designed peptides","volume":"273","author":"Blanco","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/protein\/13.11.739","article-title":"Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains","volume":"13","author":"Reiersen","year":"2000","journal-title":"Protein Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/jmr.636","article-title":"Cellular uptake [correction of utake] of the Tat peptide: An endocytosis mechanism following ionic interactions","volume":"16","author":"Vives","year":"2003","journal-title":"J. Mol. Recognit. JMR"},{"key":"ref_20","first-page":"474","article-title":"Synthetic protein transduction domains: Enhanced transduction potential in vitro and in vivo","volume":"61","author":"Ho","year":"2001","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2174\/1570159X11311020006","article-title":"Cell-penetrating Peptide-mediated therapeutic molecule delivery into the central nervous system","volume":"11","author":"Zou","year":"2013","journal-title":"Curr. Neuropharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10571-013-9999-3","article-title":"The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures","volume":"34","author":"Meloni","year":"2014","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1016\/j.bbamem.2007.06.003","article-title":"Cell-permeable peptides induce dose- and length-dependent cytotoxic effects","volume":"1768","author":"Cardozo","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2174\/1570162X13666150311164201","article-title":"Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: Role in HIV-associated neurocognitive disorders","volume":"13","author":"Fields","year":"2015","journal-title":"Curr. HIV Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1186\/1743-422X-10-358","article-title":"Roles and functions of HIV-1 Tat protein in the CNS: An overview","volume":"10","author":"Bagashev","year":"2013","journal-title":"Virol. J."},{"key":"ref_26","first-page":"460","article-title":"Disruption of GluR2\/GAPDH Complex Interaction by TAT-GluR2NT1-3-2 Peptide Protects against Neuronal Death Induced by Epilepsy","volume":"48","author":"Mi","year":"2018","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.drudis.2014.09.017","article-title":"Therapeutic applications of the cell-penetrating HIV-1 Tat peptide","volume":"20","author":"Rizzuti","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s12017-017-8441-2","article-title":"Assessment of the Neuroprotective Effects of Arginine-Rich Protamine Peptides, Poly-Arginine Peptides (R12-Cyclic, R22) and Arginine-Tryptophan-Containing Peptides Following In Vitro Excitotoxicity and\/or Permanent Middle Cerebral Artery Occlusion in Rats","volume":"19","author":"Meloni","year":"2017","journal-title":"Neuromolecular Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.neulet.2017.04.045","article-title":"Targeting neuronal nitric oxide synthase by a cell penetrating peptide Tat-LK15\/siRNA bioconjugate","volume":"650","author":"Peng","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18758","DOI":"10.3390\/ijms140918758","article-title":"Peptide-lipid interactions: Experiments and applications","volume":"14","author":"Galdiero","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s12031-016-0861-1","article-title":"The Neuroprotective Peptide Poly-Arginine-12 (R12) Reduces Cell Surface Levels of NMDA NR2B Receptor Subunit in Cortical Neurons; Investigation into the Involvement of Endocytic Mechanisms","volume":"61","author":"MacDougall","year":"2017","journal-title":"J. Mol. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1161\/STROKEAHA.115.011932","article-title":"Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives","volume":"47","author":"Holloway","year":"2016","journal-title":"Stroke"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/2045-8118-10-33","article-title":"Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC\/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies","volume":"10","author":"Eigenmann","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/jcbfm.2010.148","article-title":"Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult","volume":"31","author":"Taboada","year":"2011","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1046\/j.1471-4159.1998.71031151.x","article-title":"Basement membrane proteins influence brain capillary endothelial barrier function in vitro","volume":"71","author":"Tilling","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1097\/00004647-200006000-00009","article-title":"Inflammatory activation of human brain endothelial cells by hypoxic astrocytes in vitro is mediated by IL-1beta","volume":"20","author":"Zhang","year":"2000","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/jnr.23399","article-title":"Characterization of the NT2-derived neuronal and astrocytic cell lines as alternative in vitro models for primary human neurons and astrocytes","volume":"92","author":"Haile","year":"2014","journal-title":"J. Neurosci. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2741\/3916","article-title":"Differentiating human stem cells into neurons and glial cells for neural repair","volume":"17","author":"Selvaraj","year":"2012","journal-title":"Front Biosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"212487","DOI":"10.4061\/2011\/212487","article-title":"Patient-specific pluripotent stem cells in neurological diseases","volume":"2011","author":"Durnaoglu","year":"2011","journal-title":"Stem Cells Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/scrt219","article-title":"Human conditionally immortalized neural stem cells improve locomotor function after spinal cord injury in the rat","volume":"4","author":"Amemori","year":"2013","journal-title":"Stem Cell Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1089\/ten.2005.0522","article-title":"Superior survival and durability of neurons and astrocytes on 3-dimensional aragonite biomatrices","volume":"13","author":"Peretz","year":"2007","journal-title":"Tissue Eng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nmeth777","article-title":"A microfluidic culture platform for CNS axonal injury, regeneration and transport","volume":"2","author":"Taylor","year":"2005","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s12975-012-0201-x","article-title":"Human in vitro models of ischaemic stroke: A test bed for translation","volume":"3","author":"Antonic","year":"2012","journal-title":"Transl. Stroke Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kalafatovic, D., and Giralt, E. (2017). Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity. Molecules, 22.","DOI":"10.3390\/molecules22111929"},{"key":"ref_45","first-page":"879","article-title":"Synthesis and circular dichroism studies of HIV-1 Tat arginine rich domain analogues substituted in Arg 52 position","volume":"73","author":"Szyk","year":"1999","journal-title":"Pol. J. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.3390\/ph3041045","article-title":"Cell-Penetrating Peptides: A Comparative Study on Lipid Affinity and Cargo Delivery Properties","volume":"3","author":"Ruzza","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_47","first-page":"423","article-title":"Tat cell-penetrating peptide has the characteristics of a poly(proline) II helix in aqueous solution and in SDS micelles","volume":"10","author":"Ruzza","year":"2004","journal-title":"J. Pept. Sci. Off. Publ. Eur. Pept. Soc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/bip.10354","article-title":"NMR identification of left-handed polyproline type II helices","volume":"69","author":"Lam","year":"2003","journal-title":"Biopolymers"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12179","DOI":"10.1073\/pnas.182199699","article-title":"Mechanism by which 2,2,2-trifluoroethanol\/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study","volume":"99","author":"Roccatano","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1002\/1521-3765(20020402)8:7<1663::AID-CHEM1663>3.0.CO;2-P","article-title":"Evidence of complete hydrophobic coating of bombesin by trifluoroethanol in aqueous solution: An NMR spectroscopic and molecular dynamics study","volume":"8","author":"Diaz","year":"2002","journal-title":"Chemistry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/bip.21166","article-title":"Trifluoroethanol reveals helical propensity at analogous positions in cytoplasmic domains of three connexins","volume":"92","author":"Fort","year":"2009","journal-title":"Biopolymers"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8413","DOI":"10.1021\/bi9707133","article-title":"Mechanism of helix induction by trifluoroethanol: A framework for extrapolating the helix-forming properties of peptides from trifluoroethanol\/water mixtures back to water","volume":"36","author":"Luo","year":"1997","journal-title":"Biochemistry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1073\/pnas.60.4.1122","article-title":"Conformations of polypeptides with ionized side chains of equal length","volume":"60","author":"Krimm","year":"1968","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1021\/ja01080a015","article-title":"The Ultraviolet Circular Dichroism of Polypeptides","volume":"87","author":"Holzwarth","year":"1965","journal-title":"J. Am. Chem. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11010-016-2882-z","article-title":"Characterisation of neuroprotective efficacy of modified poly-arginine-9 (R9) peptides using a neuronal glutamic acid excitotoxicity model","volume":"426","author":"Edwards","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"72","DOI":"10.2174\/2211550111201010072","article-title":"Post-translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering","volume":"1","author":"Wang","year":"2012","journal-title":"Curr. Biotechnol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1021\/mp500495u","article-title":"Chirality switching within an anionic cell-penetrating peptide inhibits translocation without affecting preferential entry","volume":"12","author":"Yamada","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1042\/BST0350794","article-title":"all-D proline-rich cell-penetrating peptides: A preliminary in vivo internalization study","volume":"35","author":"Pujals","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.chembiol.2011.06.006","article-title":"Preferential uptake of L- versus D-amino acid cell-penetrating peptides in a cell type-dependent manner","volume":"18","author":"Verdurmen","year":"2011","journal-title":"Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.jconrel.2012.07.022","article-title":"Direct cytosolic delivery of cargoes in vivo by a chimera consisting of D- and L-arginine residues","volume":"162","author":"Ma","year":"2012","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6147","DOI":"10.1002\/anie.201101535","article-title":"Self-activation in de novo designed mimics of cell-penetrating peptides","volume":"50","author":"Som","year":"2011","journal-title":"Angew. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1002\/anie.201104624","article-title":"Protein transduction domain mimics: The role of aromatic functionality","volume":"51","author":"Som","year":"2012","journal-title":"Angew. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.vascn.2016.10.001","article-title":"Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds","volume":"83","author":"Terrasso","year":"2017","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"22213","DOI":"10.1021\/acsami.1c03709","article-title":"Lymph Node Delivery Strategy Enables the Activation of Cytotoxic T Lymphocytes and Natural Killer Cells to Augment Cancer Immunotherapy","volume":"13","author":"Jiang","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"16363","DOI":"10.1038\/s41598-018-34696-x","article-title":"Comparison of cell-based assays to quantify treatment effects of anticancer drugs identifies a new application for Bodipy-L-cystine to measure apoptosis","volume":"8","author":"Kumar","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1038\/s41598-018-19930-w","article-title":"Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition","volume":"8","author":"Rai","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S0197-0186(01)00097-3","article-title":"Substrate-dependence of reduction of MTT: A tetrazolium dye differs in cultured astroglia and neurons","volume":"40","author":"Takahashi","year":"2002","journal-title":"Neurochem. Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1006\/exnr.1994.1159","article-title":"Systemic or local administration of azide produces striatal lesions by an energy impairment-induced excitotoxic mechanism","volume":"129","author":"Brouillet","year":"1994","journal-title":"Exp. Neurol."},{"key":"ref_69","first-page":"242","article-title":"Neuroprotective effects of hydrogen sulfide on sodium azide-induced oxidative stress in PC12 cells","volume":"41","author":"Gao","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0306-4522(99)00306-1","article-title":"Effects of in vivo sodium azide administration on the immunohistochemical localization of kynurenine aminotransferase in the rat brain","volume":"94","author":"Okuno","year":"1999","journal-title":"Neuroscience"},{"key":"ref_71","first-page":"295","article-title":"Riluzole But Not Melatonin Ameliorates Acute Motor Neuron Degeneration and Moderately Inhibits SOD1-Mediated Excitotoxicity Induced Disrupted Mitochondrial Ca2+ Signaling in Amyotrophic Lateral Sclerosis","volume":"10","author":"Jaiswal","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.expneurol.2003.10.015","article-title":"Lactate induced excitotoxicity in hippocampal slice cultures","volume":"186","author":"Xiang","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_73","first-page":"725","article-title":"Influence of in vitro lactic acidosis on central nervous system neurons","volume":"37","author":"Khan","year":"1989","journal-title":"Pathol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/jcbfm.1989.70","article-title":"The effects of extracellular acidosis on neurons and glia in vitro","volume":"9","author":"Goldman","year":"1989","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainres.2010.09.007","article-title":"AP-1 inhibitory peptides attenuate in vitro cortical neuronal cell death induced by kainic acid","volume":"1360","author":"Meade","year":"2010","journal-title":"Brain Res."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Lariosa-Willingham, K.D., Rosler, E.S., Tung, J.S., Dugas, J.C., Collins, T.L., and Leonoudakis, D. (2016). A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells. BMC Res. Notes, 9.","DOI":"10.1186\/s13104-016-2220-2"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s42003-020-0765-z","article-title":"A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening","volume":"3","author":"Gupta","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1038\/510S1a","article-title":"Stroke","volume":"510","author":"Owens","year":"2014","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.neuropharm.2017.08.036","article-title":"Cell-based and pharmacological neurorestorative therapies for ischemic stroke","volume":"134","author":"Venkat","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4103\/bc.bc_12_17","article-title":"The cerebral circulation and cerebrovascular disease III: Stroke","volume":"3","author":"Chandra","year":"2017","journal-title":"Brain Circ."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jconrel.2019.07.020","article-title":"Cell-penetrating peptide: A means of breaking through the physiological barriers of different tissues and organs","volume":"309","author":"Xu","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.omtn.2017.05.004","article-title":"Tat-haFGF14-154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP\/PS1 Mice through the PI3K-CREB-IRE1alpha\/XBP1 Pathway","volume":"7","author":"Meng","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13041-018-0352-0","article-title":"Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat","volume":"11","author":"Edwards","year":"2018","journal-title":"Mol. Brain"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1073\/pnas.1614728114","article-title":"Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a","volume":"114","author":"Chassagnon","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/1389450116666150531162212","article-title":"HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions","volume":"17","author":"Hu","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/35073667","article-title":"Pathways to neuronal injury and apoptosis in HIV-associated dementia","volume":"410","author":"Kaul","year":"2001","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1046\/j.1471-4159.2001.00396.x","article-title":"HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity","volume":"78","author":"Haughey","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.mito.2004.05.009","article-title":"HIV-associated dementia, mitochondrial dysfunction, and oxidative stress","volume":"4","author":"Valcour","year":"2004","journal-title":"Mitochondrion"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1212\/WNL.0b013e318200d727","article-title":"HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: Charter Study","volume":"75","author":"Heaton","year":"2010","journal-title":"Neurology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1515\/tnsci-2017-0021","article-title":"Assessment of R18, COG1410, and APP96-110 in Excitotoxicity and Traumatic Brain Injury","volume":"8","author":"Chiu","year":"2017","journal-title":"Transl. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2012.10.004","article-title":"Fingolimod protects cultured cortical neurons against excitotoxic death","volume":"67","author":"Molinaro","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12974-015-0308-6","article-title":"FTY720 attenuates excitotoxicity and neuroinflammation","volume":"12","author":"Cipriani","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"C178","DOI":"10.1152\/ajpcell.1983.245.3.C178","article-title":"Influence of organic acids on intracellular pH","volume":"245","author":"Marrannes","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1215\/15228517-2008-106","article-title":"Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2","volume":"11","author":"Baumann","year":"2009","journal-title":"Neuro Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"23141","DOI":"10.18632\/oncotarget.8153","article-title":"The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_96","first-page":"895","article-title":"Arginine synthesis from citrulline in perivascular nerves of cerebral artery","volume":"273","author":"Chen","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7902","DOI":"10.1074\/jbc.M115.711564","article-title":"Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides","volume":"291","author":"Wang","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1096\/fj.14-269225","article-title":"Novel cell-penetrating peptide targeting mitochondria","volume":"29","author":"Cerrato","year":"2015","journal-title":"FASEB J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0006-3495(04)74101-6","article-title":"Interaction of the protein transduction domain of HIV-1 TAT with heparan sulfate: Binding mechanism and thermodynamic parameters","volume":"86","author":"Ziegler","year":"2004","journal-title":"Biophys. J."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/cgt.2008.45","article-title":"Enhanced delivery efficiency of recombinant adenovirus into tumor and mesenchymal stem cells by a novel PTD","volume":"15","author":"Youn","year":"2008","journal-title":"Cancer Gene Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/S0140-6736(20)30258-0","article-title":"Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): A multicentre, double-blind, randomised controlled trial","volume":"395","author":"Hill","year":"2020","journal-title":"Lancet"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Bu, Q., Liu, X., Hu, W., and Wang, Y. (2014). Neuroprotective effect of TAT-14-3-3epsilon fusion protein against cerebral ischemia\/reperfusion injury in rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093334"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"14727","DOI":"10.1523\/JNEUROSCI.1304-15.2015","article-title":"Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia","volume":"35","author":"Tu","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5423","DOI":"10.1523\/JNEUROSCI.22-13-05423.2002","article-title":"In Vivo Delivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis","volume":"22","author":"Cao","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/j.1527-3458.2005.tb00054.x","article-title":"TAT-GDNF in neurodegeneration and ischemic stroke","volume":"11","author":"Kilic","year":"2005","journal-title":"CNS Drug Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1038\/jcbfm.2013.126","article-title":"TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells","volume":"33","author":"Doeppner","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1159\/000076669","article-title":"The TAT protein transduction domain enhances the neuroprotective effect of glial-cell-line-derived neurotrophic factor after optic nerve transection","volume":"1","author":"Kilic","year":"2004","journal-title":"Neuro Degener. Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/brain\/awh700","article-title":"Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence","volume":"129","author":"Pei","year":"2006","journal-title":"Brain"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/sj.mt.6300045","article-title":"Protein transduction domain-mediated delivery of QBP1 suppresses polyglutamine-induced neurodegeneration in vivo","volume":"15","author":"Popiel","year":"2007","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"414729","DOI":"10.1155\/2011\/414729","article-title":"Mechanisms of cellular uptake of cell-penetrating peptides","volume":"2011","author":"Madani","year":"2011","journal-title":"J. Biophys."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1208\/s12248-008-9055-2","article-title":"CNS delivery via adsorptive transcytosis","volume":"10","author":"Herve","year":"2008","journal-title":"AAPS J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fneur.2020.00108","article-title":"Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents with a Multimodal Mechanism of Action","volume":"11","author":"Meloni","year":"2020","journal-title":"Front Neurol"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"12684","DOI":"10.1073\/pnas.1411817111","article-title":"Label-free probe of HIV-1 TAT peptide binding to mimetic membranes","volume":"111","author":"Rao","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1586\/14737175.2016.1150180","article-title":"The neuroprotective potential of arginine-rich peptides for the acute treatment of traumatic brain injury","volume":"16","author":"Chiu","year":"2016","journal-title":"Expert Rev. Neurother."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"16880","DOI":"10.1074\/jbc.M111.318063","article-title":"Cell-penetrating Peptides Split into Two Groups Based on Modulation of Intracellular Calcium Concentration","volume":"287","author":"Lorents","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1128\/jvi.70.3.1475-1480.1996","article-title":"Identification of a human immunodeficiency virus type 1 tat epitope that is neuroexcitatory and neurotoxic","volume":"70","author":"Nath","year":"1996","journal-title":"J. Virol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Ramos-Molina, B., Lick, A.N., Nasrolahi Shirazi, A., Oh, D., Tiwari, R., El-Sayed, N.S., Parang, K., and Lindberg, I. (2015). Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130417"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3926","DOI":"10.1021\/acs.jctc.6b00567","article-title":"Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model","volume":"12","author":"Debiec","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/1097-0282(2000)56:4<275::AID-BIP10024>3.0.CO;2-E","article-title":"Theory and applications of the generalized Born solvation model in macromolecular simulations","volume":"56","author":"Tsui","year":"2000","journal-title":"Biopolymers"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0263-7855(96)00009-4","article-title":"MOLMOL: A program for display and analysis of macromolecular structures","volume":"14","author":"Koradi","year":"1996","journal-title":"J. Mol. Graph."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/6086\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:11:04Z","timestamp":1760163064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/6086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,4]]},"references-count":122,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22116086"],"URL":"https:\/\/doi.org\/10.3390\/ijms22116086","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,4]]}}}