{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:33:45Z","timestamp":1772138025468,"version":"3.50.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":55,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM138146"],"award-info":[{"award-number":["R35GM138146"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DBI2208679"],"award-info":[{"award-number":["DBI2208679"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein side-chain packing (PSCP), the problem of predicting side-chain conformations given a fixed backbone structure, has important implications in the modeling of structures and interactions. However, despite the groundbreaking progress in protein structure prediction pioneered by AlphaFold, the existing PSCP methods still rely on experimental inputs, and do not leverage AlphaFold-predicted backbone coordinates to enable PSCP at scale. Here, we perform a large-scale benchmarking of the predictive performance of various PSCP methods on public datasets from multiple rounds of the Critical Assessment of Structure Prediction challenges using a diverse set of evaluation metrics. Empirical results demonstrate that the PSCP methods perform well in packing the side-chains with experimental inputs, but they fail to generalize in repacking AlphaFold-generated structures. We additionally explore the effectiveness of leveraging the self-assessment confidence scores from AlphaFold by implementing a backbone confidence-aware integrative approach. While such a protocol often leads to performance improvement by attaining modest yet statistically significant accuracy gains over the AlphaFold baseline, it does not yield consistent and pronounced improvements. Our study highlights the recent advances and remaining challenges in PSCP in the post-AlphaFold era.<\/jats:p>","DOI":"10.1093\/bib\/bbaf297","type":"journal-article","created":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T07:40:43Z","timestamp":1749282043000},"source":"Crossref","is-referenced-by-count":0,"title":["To pack or not to pack: revisiting protein side-chain packing in the post-AlphaFold era"],"prefix":"10.1093","volume":"26","author":[{"given":"Sriniketh","family":"Vangaru","sequence":"first","affiliation":[{"name":"Department of Computer Science, Virginia Tech , 1160 Torgersen Hall, 620 Drillfield Drive, Blacksburg, VA 24061 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9630-0141","authenticated-orcid":false,"given":"Debswapna","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Virginia Tech , 1160 Torgersen Hall, 620 Drillfield Drive, Blacksburg, VA 24061 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"2025062515420556300_ref1","doi-asserted-by":"publisher","first-page":"37024","DOI":"10.1038\/srep37024","article-title":"Quantifying side-chain conformational variations in protein structure","volume":"6","author":"Miao","year":"2016","journal-title":"Sci Rep"},{"key":"2025062515420556300_ref2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0079-6107(01)00005-0","article-title":"The interrelationships of side-chain and main-chain conformations in proteins","volume":"76","author":"Chakrabarti","year":"2001","journal-title":"Prog Biophys Mol Biol"},{"key":"2025062515420556300_ref3","doi-asserted-by":"publisher","first-page":"aag1465","DOI":"10.1126\/science.aag1465","article-title":"Posttranslational mutagenesis: a chemical strategy for exploring protein side-chain diversity","volume":"354","author":"Wright","year":"2016","journal-title":"Science"},{"key":"2025062515420556300_ref4","doi-asserted-by":"publisher","first-page":"2062","DOI":"10.1016\/j.bpj.2019.04.017","article-title":"Rotamer dynamics: analysis of rotamers in molecular dynamics simulations of proteins","volume":"116","author":"Haddad","year":"2019","journal-title":"Biophys J"},{"key":"2025062515420556300_ref5","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.1073\/pnas.1012668108","article-title":"Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction","volume":"108","author":"Bachmann","year":"2011","journal-title":"Proc Natl Acad Sci"},{"key":"2025062515420556300_ref6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0228245","article-title":"SPECS: integration of side-chain orientation and global distance-based measures for improved evaluation of protein structural models","volume":"15","author":"Alapati","year":"2020","journal-title":"PloS One"},{"key":"2025062515420556300_ref7","doi-asserted-by":"publisher","first-page":"2791","DOI":"10.1093\/bioinformatics\/btw316","article-title":"UniCon3D: de novo protein structure prediction using united-residue conformational search via stepwise, probabilistic sampling","volume":"32","author":"Bhattacharya","year":"2016","journal-title":"Bioinformatics"},{"key":"2025062515420556300_ref8","doi-asserted-by":"publisher","first-page":"11982","DOI":"10.1021\/jacs.0c13118","article-title":"Effects of weak nonspecific interactions with ATP on proteins","volume":"143","author":"Nishizawa","year":"2021","journal-title":"J Am Chem Soc"},{"key":"2025062515420556300_ref9","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/0022-2836(78)90229-2","article-title":"A survey of amino acid side-chain interactions in 21 proteins","volume":"118","author":"Warme","year":"1978","journal-title":"J Mol Biol"},{"key":"2025062515420556300_ref10","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1093\/nar\/gku1344","article-title":"Absolute binding-free energies between standard RNA\/DNA nucleobases and amino-acid sidechain analogs in different environments","volume":"43","author":"Ruiter","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2025062515420556300_ref11","first-page":"vbad070","article-title":"PIQLE: protein\u2013protein interface quality estimation by deep graph learning of multimeric interaction geometries. 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