{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T07:40:38Z","timestamp":1758699638682,"version":"3.44.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":9,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020, MOSBRI","award":["EFA080\/01"],"award-info":[{"award-number":["EFA080\/01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The stability of protein interfaces influences protein dynamics and unfolding cooperativity. Although in some cases the dynamics of proteins can be deduced from their topology, much of the stability of an interface is related to the complementarity of the interacting parts. It is also important to note that proteins that display non-cooperative unfolding cannot be rationally stabilized unless the regions that unfold first are known. Being able to identify protein interfaces that are significantly less stable would contribute to our understanding of protein dynamics and be very valuable in guiding the rational stabilization of proteins with non-two-state unfolding equilibria.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We introduce ProteinLIPs, a web server that detects interfaces of high polarity and low packing density, termed LIPs. Each LIP consist of a continuous sequence segment (mLIP) plus its contacting residues (cLIP). ProteinLIPs scans monomeric and oligomeric proteins and provides graphical sequence profiles and interactive 3D visualizations of the detected LIPs. Statistical analysis of 53 protein domains from 10 superfamilies shows the two parts of a LIP present distinct characteristics. mLIPs are conserved, structurally unstable and enriched in polar residues, whereas cLIPs are more stable, less conserved, and enriched in apolar residues. Besides, cLIPs are enriched in small-molecule binding site residues, suggesting they play a role in ligand interaction, likely facilitated by instability of the associated mLIPs. ProteinLIPs provides a user-friendly platform for the automated identification and visualization of LIPs and can be used to guide the engineering of non-two-state proteins where LIPs constitute preferential targets for thermostabilization.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>ProteinLIPs is publicly available at https:\/\/lips.bifi.es\/.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf499","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:33:49Z","timestamp":1757525629000},"source":"Crossref","is-referenced-by-count":0,"title":["ProteinLIPs: a web server for identifying highly polar and poorly packed interfaces in proteins"],"prefix":"10.1093","volume":"41","author":[{"given":"Helena","family":"Garc\u00eda-Cebollada","sequence":"first","affiliation":[{"name":"Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit GBsC-CSIC, University of Zaragoza, 50018 Zaragoza,","place":["Spain"]},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Ciencias, University of Zaragoza, 50009 Zaragoza,","place":["Spain"]}]},{"given":"Alfonso","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit GBsC-CSIC, University of Zaragoza, 50018 Zaragoza,","place":["Spain"]}]},{"given":"Vladimir E","family":"Angarica","sequence":"additional","affiliation":[{"name":"Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit GBsC-CSIC, University of Zaragoza, 50018 Zaragoza,","place":["Spain"]},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Ciencias, University of Zaragoza, 50009 Zaragoza,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1896-7805","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Galano-Frutos","sequence":"additional","affiliation":[{"name":"Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit GBsC-CSIC, University of Zaragoza, 50018 Zaragoza,","place":["Spain"]},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Ciencias, University of Zaragoza, 50009 Zaragoza,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2879-9200","authenticated-orcid":false,"given":"Javier","family":"Sancho","sequence":"additional","affiliation":[{"name":"Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit GBsC-CSIC, University of Zaragoza, 50018 Zaragoza,","place":["Spain"]},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Ciencias, University of Zaragoza, 50009 Zaragoza,","place":["Spain"]},{"name":"Aragon Health Research Institute (IIS Arag\u00f3n), 50009 Zaragoza,","place":["Spain"]}]}],"member":"286","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2025092403220612700_btaf499-B1","doi-asserted-by":"crossref","first-page":"e1005242","DOI":"10.1371\/journal.pcbi.1005242","article-title":"Alpha helices are more robust to mutations than beta strands","volume":"12","author":"Abrus\u00e1n","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"2025092403220612700_btaf499-B2","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/0958-1669(94)90048-5","article-title":"Core-packing constraints, hydrophobicity and protein design","volume":"5","author":"Baldwin","year":"1994","journal-title":"Curr Opin Biotechnol"},{"key":"2025092403220612700_btaf499-B3","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/pro.3779","article-title":"ConSurf-DB: an accessible repository for the evolutionary conservation patterns of the majority of PDB proteins","volume":"29","author":"Ben Chorin","year":"2020","journal-title":"Protein Sci"},{"key":"2025092403220612700_btaf499-B4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.jmb.2004.08.081","article-title":"Structure of stable protein folding intermediates by equilibrium \u03d5-analysis: the apoflavodoxin thermal intermediate","volume":"344","author":"Campos","year":"2004","journal-title":"J Mol Biol"},{"key":"2025092403220612700_btaf499-B5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jmb.2004.09.047","article-title":"Do proteins always benefit from a stability increase? Relevant and residual stabilisation in a three-state protein by charge optimisation","volume":"344","author":"Campos","year":"2004","journal-title":"J Mol Biol"},{"key":"2025092403220612700_btaf499-B6","volume-title":"Statistical Power Analysis for the Behavioral Sciences","author":"Cohen","year":"1988","edition":"2nd edn"},{"key":"2025092403220612700_btaf499-B7","doi-asserted-by":"crossref","first-page":"e48212","DOI":"10.1371\/journal.pone.0048212","article-title":"Protein dynamics governed by interfaces of high polarity and low packing density","volume":"7","author":"Espinosa-Angarica","year":"2012","journal-title":"PLoS One"},{"key":"2025092403220612700_btaf499-B8","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1093\/bioinformatics\/btab034","article-title":"SWOTein: a structure-based approach to predict stability strengths and weaknesses of prOTEINs","volume":"37","author":"Hou","year":"2021","journal-title":"Bioinformatics"},{"key":"2025092403220612700_btaf499-B9","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1021\/acs.jctc.3c00036","article-title":"Enzyme stability-activity trade-off: new insights from protein stability weaknesses and evolutionary conservation","volume":"19","author":"Hou","year":"2023","journal-title":"J Chem Theory Comput"},{"year":"1993","author":"Hubbard","key":"2025092403220612700_btaf499-B10"},{"key":"2025092403220612700_btaf499-B11","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"2025092403220612700_btaf499-B12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/1479-7364-4-3-207","article-title":"The CATH database","volume":"4","author":"Knudsen","year":"2010","journal-title":"Hum Genomics"},{"key":"2025092403220612700_btaf499-B13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/11560500_15","volume-title":"Computational Life Sciences","author":"Krissinel","year":"2005"},{"key":"2025092403220612700_btaf499-B14","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.jmb.2007.05.022","article-title":"Inference of macromolecular assemblies from crystalline state","volume":"372","author":"Krissinel","year":"2007","journal-title":"J Mol Biol"},{"key":"2025092403220612700_btaf499-B100","doi-asserted-by":"publisher","first-page":"19021","DOI":"10.1039\/c7cp02606d","article-title":"Direct examination of the relevance for folding, binding and electron transfer of a conserved protein folding intermediate","volume-title":"Phys Chem Chem Phys","author":"Lamazares E, Vega S, Ferreira P","year":"2017"},{"key":"2025092403220612700_btaf499-B15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.sbi.2020.10.016","article-title":"Unraveling protein\u2019s structural dynamics: from configurational dynamics to ensemble switching guides functional mesoscale assemblies","volume":"66","author":"Medina","year":"2021","journal-title":"Curr Opin Struct Biol"},{"key":"2025092403220612700_btaf499-B16","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1006\/jmbi.1996.0506","article-title":"Analysis of domain structural class using an automated class assignment protocol","volume":"262","author":"Michie","year":"1996","journal-title":"J Mol Biol"},{"key":"2025092403220612700_btaf499-B17","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s00018-005-5514-4","article-title":"Flavodoxins: sequence, folding, binding, function and beyond","volume":"63","author":"Sancho","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"2025092403220612700_btaf499-B18","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1100\/tsw.2002.196","article-title":"The \u2018relevant\u2019 stability of proteins with equilibrium intermediates","volume":"2","author":"Sancho","year":"2002","journal-title":"ScientificWorldJournal"},{"key":"2025092403220612700_btaf499-B19","doi-asserted-by":"crossref","first-page":"5526","DOI":"10.1093\/bioinformatics\/btaa1012","article-title":"RCSB protein data bank 1D tools and services","volume":"36","author":"Segura","year":"2021","journal-title":"Bioinformatics"},{"key":"2025092403220612700_btaf499-B20","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1073\/pnas.92.2.452","article-title":"A relationship between protein stability and protein function","volume":"92","author":"Shoichet","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025092403220612700_btaf499-B21","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3109\/07388551.2016.1144045","article-title":"Defying the activity\u2013stability trade-off in enzymes: taking advantage of entropy to enhance activity and thermostability","volume":"37","author":"Siddiqui","year":"2017","journal-title":"Crit Rev Biotechnol"},{"key":"2025092403220612700_btaf499-B22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2307\/2331554","article-title":"The probable error of a mean","volume":"6","author":"Student","year":"1908","journal-title":"Biometrika"},{"key":"2025092403220612700_btaf499-B23","doi-asserted-by":"crossref","first-page":"e80635","DOI":"10.1371\/journal.pone.0080635","article-title":"Maximum allowed solvent accessibilites of residues in proteins","volume":"8","author":"Tien","year":"2013","journal-title":"PLoS One"},{"key":"2025092403220612700_btaf499-B24","doi-asserted-by":"crossref","first-page":"D364","DOI":"10.1093\/nar\/gku1028","article-title":"A series of PDB-related databanks for everyday needs","volume":"43","author":"Touw","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2025092403220612700_btaf499-B25","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1006\/jmbi.1999.2829","article-title":"The packing density in proteins: standard radii and volumes","volume":"290","author":"Tsai","year":"1999","journal-title":"J Mol Biol"},{"key":"2025092403220612700_btaf499-B26","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jmb.2004.11.072","article-title":"Calculation of standard atomic volumes for RNA and comparison with proteins: RNA is packed more tightly","volume":"346","author":"Voss","year":"2005","journal-title":"J Mol Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaf499\/64237223\/btaf499.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/9\/btaf499\/64237223\/btaf499.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/9\/btaf499\/64237223\/btaf499.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T07:22:14Z","timestamp":1758698534000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btaf499\/8250704"}},"subtitle":[],"editor":[{"given":"Jianlin","family":"Cheng","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,9,1]]},"references-count":27,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaf499","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,9,1]]},"article-number":"btaf499"}}