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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Deer Horn Glue is rich in collagen- and tissue-derived proteins, but the link between its experimentally observed proteome, the theoretical peptide sequence space derived from that proteome, and bone-related molecular targets remains poorly defined. This study established a proteomics-guided multiscale computational workflow to prioritize putative receptor activator of nuclear factor-\u03baB ligand (RANKL)-binding peptide candidates generated from proteins identified in one Deer Horn Glue sample. The Deer Horn Glue proteome was characterized by liquid chromatography\u2013tandem mass spectrometry (LC-MS\/MS). Experimentally identified proteins were subjected to in silico tryptic digestion and stepwise activity, safety, and physicochemical screening. All 49 retained candidates underwent global and interface-focused docking. Five prioritized peptides were examined by AlphaFold 3, three independently seeded 200 ns molecular dynamics simulations per complex, entropy-omitted molecular mechanics\/generalized Born surface area (MM\/GBSA) analysis, residue decomposition, and locally relaxed computational alanine substitution analysis. Proteomic analysis retained 707 target protein groups and generated 24,575 nonredundant theoretical peptide sequences. Stepwise screening retained 49 candidates. Global and interface-focused docking rankings showed modest agreement, and the expanded interface analysis identified additional candidates while retaining GASLQDWDFGK as the top-ranked sequence. Across three independent simulations, GASLQDWDFGK showed consistently low peptide root-mean-square deviation (RMSD), whereas HEFSVDMTCEGCSNAVTR formed the largest mean number of interfacial hydrogen bonds. Their entropy-omitted MM\/GBSA estimates were generally the most favorable, although the order varied among simulations. Locally relaxed alanine substitutions highlighted reproducible energy-sensitive positions for experimental testing. By linking an experimentally observed Deer Horn Glue proteome to multiscale structural analysis, this workflow provides a traceable and reproducible strategy for prioritizing testable peptide\u2013RANKL interaction hypotheses. The five candidates remain theoretical products of in silico digestion and require targeted detection, direct binding, and functional validation.<\/jats:p>","DOI":"10.3390\/ijms27188255","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:07:29Z","timestamp":1789574849000},"page":"8255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomics-Guided Computational Prioritization of Putative RANKL-Binding Peptides from Proteins Identified in Deer Horn Glue"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2924-2330","authenticated-orcid":false,"given":"Zhonghao","family":"Fan","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6384-6016","authenticated-orcid":false,"given":"Tiefeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, National Engineering Research Center for Modernization of Traditional Chinese Medicine Qilu Resources Branch, Shandong Center of Technology Innovation for Plant-Based Protein, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8968-3419","authenticated-orcid":false,"given":"Heng","family":"Aik Teng","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, INTI International University, Nilai 71800, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-6648","authenticated-orcid":false,"given":"Haitao","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, National Engineering Research Center for Modernization of Traditional Chinese Medicine Qilu Resources Branch, Shandong Center of Technology Innovation for Plant-Based Protein, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Kun","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1268-4625","authenticated-orcid":false,"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, National Engineering Research Center for Modernization of Traditional Chinese Medicine Qilu Resources Branch, Shandong Center of Technology Innovation for Plant-Based Protein, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Jingwen","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Science and Education, Shandong Academy of Chinese Medicine, National Engineering Research Center for Modernization of Traditional Chinese Medicine Qilu Resources Branch, Shandong Center of Technology Innovation for Plant-Based Protein, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, National Engineering Research Center for Modernization of Traditional Chinese Medicine Qilu Resources Branch, Shandong Center of Technology Innovation for Plant-Based Protein, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","unstructured":"Chinese Pharmacopoeia Commission (2025). 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