{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:59:56Z","timestamp":1790258396227,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100015439","name":"Centres de Recerca de Catalunya","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015439","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Peptide\u2013protein interactions are fundamental to many biological processes, and peptide design is gaining interest due to its therapeutic potential. This has led to the emergence of various structural databases, such as PepBDB and Peptipedia, that classify peptides as polypeptides with fewer than 50 amino acids. These databases provide valuable starting points for studying peptide recognition by protein partners and are widely used for machine learning applications, docking, and scoring functions. However, under such a length definition for peptides, we have very different cases that are likely to confound the analysis of peptide binding, including miniproteins, peptide\u2013peptide complexes, intramolecular peptide disulfide bonds, intermolecular disulfide bridges, and proteins undergoing internal cleavage, such as serpins, as well as non\u2010natural amino acids and covalently bound cofactors. Here, we present a rigorous classification of peptide\u2013protein complexes to generate datasets suitable for comparative energetic analysis with a focus on peptides that are unstructured in the absence of their target protein. The analysis of this dataset shows that peptide binding is typically driven by a small number of hotspot residues mainly enriched in aromatic and bulky hydrophobic side chains. Their number of hotspots and their spatial organization depend on peptide length, secondary structure, and covalent constraints. Short peptides rely on central anchor regions, whereas longer peptides distribute hotspots more broadly, with helices showing periodic spacing and \u03b2\u2010strands relying more on backbone\u2010mediated stabilization. Disulfide bonds further decrease the number of hotspots per peptide length by either pre\u2010organizing the peptide or acting as covalent anchors. This work provides a curated resource and general principles for peptide recognition. It highlights the importance of structurally classifying peptide\u2013protein complexes to avoid bias in downstream computational and machine\u2010learning applications.<\/jats:p>","DOI":"10.1002\/pro.70779","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:24:41Z","timestamp":1789467881000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A curated structural dataset of peptide\u2013protein complexes reveals biases in existing datasets and principles of peptide binding"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3654-0378","authenticated-orcid":false,"given":"Rahma","family":"Hamdani","sequence":"first","affiliation":[{"name":"Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-5445","authenticated-orcid":false,"given":"Javier","family":"Delgado","sequence":"additional","affiliation":[{"name":"Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5276-1392","authenticated-orcid":false,"given":"Luis","family":"Serrano","sequence":"additional","affiliation":[{"name":"Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology  Barcelona Spain"},{"name":"Universitat Pompeu Fabra (UPF)  Barcelona Spain"},{"name":"ICREA  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"21","key":"e_1_2_10_2_1","first-page":"4746","article-title":"The analytical flory random coil is a simple\u2010to\u2010use reference model for unfolded and disordered proteins","volume":"127","author":"Alston 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