{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T08:36:27Z","timestamp":1773390987762,"version":"3.50.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LD22H300004"],"award-info":[{"award-number":["LD22H300004"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Development Fund of Macau","award":["0177\/2023\/RIA3"],"award-info":[{"award-number":["0177\/2023\/RIA3"]}]}],"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>Cyclic peptides containing unnatural amino acids possess many excellent properties and have become promising candidates in drug discovery. Therefore, accurately predicting the 3D structures of cyclic peptides containing unnatural residues will significantly advance the development of cyclic peptide-based therapeutics. Although deep learning-based structural prediction models have made tremendous progress, these models still cannot predict the structures of cyclic peptides containing unnatural amino acids. To address this gap, we introduce a novel model, HighFold2, built upon the AlphaFold-Multimer framework. HighFold2 first extends the pre-defined rigid groups and their initial atomic coordinates from natural amino acids to unnatural amino acids, thus enabling structural prediction for these residues. Then, it incorporates an additional neural network to characterize the atom-level features of peptides, allowing for multi-scale modeling of peptide molecules while enabling the distinction between various unnatural amino acids. Besides, HighFold2 constructs a relative position encoding matrix for cyclic peptides based on different cyclization constraints. Except for training using spatial structures with unnatural amino acids, HighFold2 also parameterizes the unnatural amino acids to relax the predicted structure by energy minimization for clash elimination. Extensive empirical experiments demonstrate that HighFold2 can accurately predict the 3D structures of cyclic peptide monomers containing unnatural amino acids and their complexes with proteins, with the median RMSD for C\u03b1 reaching 1.891\u00a0\u00c5. All these results indicate the effectiveness of HighFold2, representing a significant advancement in cyclic peptide-based drug discovery.<\/jats:p>","DOI":"10.1093\/bib\/bbaf202","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T07:33:54Z","timestamp":1745220834000},"source":"Crossref","is-referenced-by-count":6,"title":["Predicting the structures of cyclic peptides containing unnatural amino acids by HighFold2"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5155-1605","authenticated-orcid":false,"given":"Cheng","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University of Technology , Chaowang Road, Gongshu District, Hangzhou 310014 ,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8779-7449","authenticated-orcid":false,"given":"Sen","family":"Cao","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences, Macao Polytechnic University , R. de Lu\u00eds Gonzaga Gomes, Macao 999078 ,","place":["China"]}]},{"given":"Tianfeng","family":"Shang","sequence":"additional","affiliation":[{"name":"Artificial Intelligence Department, Shenzhen Highslab Therapeutics. Inc , Guangke 1st Road, Pingshan District, Shenzhen 518000 ,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4632-4364","authenticated-orcid":false,"given":"Jingjing","family":"Guo","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences, Macao Polytechnic University , R. de Lu\u00eds Gonzaga Gomes, Macao 999078 ,","place":["China"]}]},{"given":"An","family":"Su","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University of Technology , Chaowang Road, Gongshu District, Hangzhou 310014 ,","place":["China"]}]},{"given":"Chengxi","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chemical and Biological Engineering, Zhejiang University , Yuhangtang Road, Xihu District, Hangzhou 310027 ,","place":["China"]}]},{"given":"Hongliang","family":"Duan","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences, Macao Polytechnic University , R. de Lu\u00eds Gonzaga Gomes, Macao 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