{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T21:09:27Z","timestamp":1774732167373,"version":"3.50.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"W1","license":[{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004442","name":"National Science Centre, Poland","doi-asserted-by":"publisher","award":["OPUS 2016\/23\/B\/NZ2\/03247"],"award-info":[{"award-number":["OPUS 2016\/23\/B\/NZ2\/03247"]}],"id":[{"id":"10.13039\/501100004442","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite recent advances in research, the mechanism of Alzheimer's disease is not fully understood yet. Understanding the process of cleavage and then trimming of peptide substrates, can help selectively block \u03b3-secretase (GS) to stop overproduction of the amyloidogenic products. Our GS-SMD server (https:\/\/gs-smd.biomodellab.eu\/) allows cleaving and unfolding of all currently known GS substrates (more than 170 peptide substrates). The substrate structure is obtained by threading of the substrate sequence into the known structure of GS complex. The simulations are performed in an implicit water-membrane environment so they are performed rather quickly, 2\u20136 h per job, depending on the mode of calculations (part of GS complex or the whole structure). It is also possible to introduce mutations to the substrate and GS and pull any part of the substrate in any direction using the steered molecular dynamics (SMD) simulations with constant velocity. The obtained trajectories are visualized and analyzed in the interactive way. One can also compare multiple simulations using the interaction frequency analysis. GS-SMD server can be useful for revealing mechanisms of substrate unfolding and role of mutations in this process.<\/jats:p>","DOI":"10.1093\/nar\/gkad409","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T20:22:55Z","timestamp":1684527775000},"page":"W251-W262","source":"Crossref","is-referenced-by-count":3,"title":["GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the \u03b3-secretase complex"],"prefix":"10.1093","volume":"51","author":[{"given":"Urszula","family":"Orze\u0142","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawe\u0142","family":"Pasznik","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Przemys\u0142aw","family":"Miszta","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Lorkowski","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szymon","family":"Niewieczerza\u0142","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Jakowiecki","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3147-3858","authenticated-orcid":false,"given":"S\u0142awomir","family":"Filipek","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw , Warsaw , Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"2023070505031410000_B1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.nbd.2014.07.011","article-title":"Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques","volume":"71","author":"Pensalfini","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"2023070505031410000_B2","doi-asserted-by":"crossref","first-page":"292","DOI":"10.15698\/cst2018.11.162","article-title":"Making the final cut: pathogenic amyloid-beta peptide generation by gamma-secretase","volume":"2","author":"Steiner","year":"2018","journal-title":"Cell Stress"},{"key":"2023070505031410000_B3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-170628","article-title":"Complexity and selectivity of gamma-secretase cleavage on multiple substrates: consequences in Alzheimer's disease and cancer","volume":"61","author":"Medoro","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"2023070505031410000_B4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.semcdb.2020.05.019","article-title":"The substrate repertoire of gamma-secretase\/presenilin","volume":"105","author":"Guner","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"2023070505031410000_B5","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3390\/molecules26020388","article-title":"Probing mechanisms and therapeutic potential of gamma-secretase in Alzheimer's disease","volume":"26","author":"Wolfe","year":"2021","journal-title":"Molecules"},{"key":"2023070505031410000_B6","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/nrd3842-c2","article-title":"A new roadmap for drug development for Alzheimer's disease","volume":"13","author":"Becker","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023070505031410000_B7","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1080\/1061186X.2018.1474361","article-title":"Drug development for Alzheimer's disease: review","volume":"27","author":"Lao","year":"2019","journal-title":"J. Drug Target."},{"key":"2023070505031410000_B8","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1073\/pnas.1037392100","article-title":"Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2","volume":"100","author":"Kimberly","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2023070505031410000_B9","doi-asserted-by":"crossref","first-page":"eaaw0930","DOI":"10.1126\/science.aaw0930","article-title":"Recognition of the amyloid precursor protein by human gamma-secretase","volume":"363","author":"Zhou","year":"2019","journal-title":"Science"},{"key":"2023070505031410000_B10","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s41586-018-0813-8","article-title":"Structural basis of Notch recognition by human gamma-secretase","volume":"565","author":"Yang","year":"2019","journal-title":"Nature"},{"key":"2023070505031410000_B11","doi-asserted-by":"crossref","first-page":"6215","DOI":"10.1021\/jacs.1c10533","article-title":"Mechanism of tripeptide trimming of amyloid beta-peptide 49 by gamma-secretase","volume":"144","author":"Bhattarai","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2023070505031410000_B12","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1021\/acschemneuro.2c00563","article-title":"Elucidating the protonation state of the gamma-secretase catalytic dyad","volume":"14","author":"Guzman-Ocampo","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"2023070505031410000_B13","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.3390\/ijms24031835","article-title":"The binding of different substrate molecules at the docking site and the active site of gamma-secretase can trigger toxic events in sporadic and familial Alzheimer's disease","volume":"24","author":"Svedruzic","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2023070505031410000_B14","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3390\/pharmaceutics13040514","article-title":"Structural analysis of the simultaneous activation and inhibition of gamma-secretase activity in the development of drugs for Alzheimer's disease","volume":"13","author":"Svedruzic","year":"2021","journal-title":"Pharmaceutics"},{"key":"2023070505031410000_B15","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.3390\/ijms24043970","article-title":"Specific mutations near the amyloid precursor protein cleavage site increase gamma-secretase sensitivity and modulate amyloid-beta production","volume":"24","author":"Suzuki","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2023070505031410000_B16","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1021\/acscentsci.0c00296","article-title":"Mechanisms of gamma-secretase activation and substrate processing","volume":"6","author":"Bhattarai","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"2023070505031410000_B17","doi-asserted-by":"crossref","first-page":"649990","DOI":"10.3389\/fmolb.2021.649990","article-title":"Protein predictive modeling and simulation of mutations of Presenilin-1 familial Alzheimer's disease on the orthosteric site","volume":"8","author":"Soto-Ospina","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"2023070505031410000_B18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4103\/1673-5374.313016","article-title":"Presenilin mutations and their impact on neuronal differentiation in Alzheimer's disease","volume":"17","author":"Hernandez-Sapiens","year":"2022","journal-title":"Neural Regen. Res."},{"key":"2023070505031410000_B19","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"2023070505031410000_B20","doi-asserted-by":"crossref","first-page":"e17578","DOI":"10.7554\/eLife.17578","article-title":"The amyloid-beta forming tripeptide cleavage mechanism of gamma-secretase","volume":"5","author":"Bolduc","year":"2016","journal-title":"Elife"},{"key":"2023070505031410000_B21","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: the universal protein knowledgebase in 2021","volume":"49","author":"UniProt Consortium","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2023070505031410000_B22","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"2023070505031410000_B23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2023070505031410000_B24","doi-asserted-by":"crossref","first-page":"167207","DOI":"10.1016\/j.jmb.2021.167207","article-title":"Single-molecule force spectroscopy of protein folding","volume":"433","author":"Petrosyan","year":"2021","journal-title":"J. Mol. Biol."},{"key":"2023070505031410000_B25","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/cm.21692","article-title":"Studying the rhodopsin-like G protein-coupled receptors by atomic force microscopy","volume":"78","author":"Fang","year":"2021","journal-title":"Cytoskeleton (Hoboken)"},{"key":"2023070505031410000_B26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1042\/ETLS20200255","article-title":"Applications of atomic force microscopy in modern biology","volume":"5","author":"Nandi","year":"2021","journal-title":"Emerg. Top. Life Sci."},{"key":"2023070505031410000_B27","doi-asserted-by":"crossref","first-page":"W576","DOI":"10.1093\/nar\/gkv402","article-title":"NGL Viewer: a web application for molecular visualization","volume":"43","author":"Rose","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023070505031410000_B28","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1093\/bioinformatics\/bty419","article-title":"NGL viewer: web-based molecular graphics for large complexes","volume":"34","author":"Rose","year":"2018","journal-title":"Bioinformatics"},{"key":"2023070505031410000_B29","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/prot.10410","article-title":"Effective energy function for proteins in lipid membranes","volume":"52","author":"Lazaridis","year":"2003","journal-title":"Proteins"},{"key":"2023070505031410000_B30","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"2023070505031410000_B31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/(SICI)1097-0134(19990501)35:2<133::AID-PROT1>3.0.CO;2-N","article-title":"Effective energy function for proteins in solution","volume":"35","author":"Lazaridis","year":"1999","journal-title":"Proteins"},{"key":"2023070505031410000_B32","doi-asserted-by":"crossref","first-page":"W247","DOI":"10.1093\/nar\/gkab434","article-title":"GPCRsignal: webserver for analysis of the interface between G-protein-coupled receptors and their effector proteins by dynamics and mutations","volume":"49","author":"Miszta","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2023070505031410000_B33","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"2023070505031410000_B34","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: the biomolecular simulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. Chem."},{"key":"2023070505031410000_B35","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":"2023070505031410000_B36","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1021\/acs.jctc.8b01066","article-title":"CHARMM-GUI membrane builder for complex biological membrane simulations with glycolipids and lipoglycans","volume":"15","author":"Lee","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"2023070505031410000_B37","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1074\/jbc.M111.274142","article-title":"Comparative lipidomic analysis of mouse and human brain with Alzheimer disease","volume":"287","author":"Chan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023070505031410000_B38","doi-asserted-by":"crossref","first-page":"D370","DOI":"10.1093\/nar\/gkr703","article-title":"OPM database and PPM web server: resources for positioning of proteins in membranes","volume":"40","author":"Lomize","year":"2012","journal-title":"Nucleic Acids Res."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/51\/W1\/W251\/50737084\/gkad409.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/51\/W1\/W251\/50737084\/gkad409.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T12:02:12Z","timestamp":1688558532000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/51\/W1\/W251\/7173862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,19]]},"references-count":38,"journal-issue":{"issue":"W1","published-online":{"date-parts":[[2023,5,19]]},"published-print":{"date-parts":[[2023,7,5]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkad409","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,7,5]]},"published":{"date-parts":[[2023,5,19]]}}}