{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:01:04Z","timestamp":1785243664145,"version":"3.55.0"},"reference-count":90,"publisher":"American Chemical Society (ACS)","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12175195"],"award-info":[{"award-number":["12175195"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2025YFC2311702"],"award-info":[{"award-number":["2025YFC2311702"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371299"],"award-info":[{"award-number":["32371299"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The regulation of conformational stability in multidomain proteins (MDP) is a central challenge in protein engineering with major implications for antigen optimization, enzyme activity modulation, and signal transduction. The function of these proteins depends on the properties of their constituent domains as well as on interdomain orientation and interface rearrangement during conformational transitions. Previous studies show that conformational transition is largely governed by changes in a small number of key residue pairs. However, such dynamic inter-residue contacts are typically sparse, transient, and coupled to large-scale domain motions, making them difficult to resolve directly by experiments or simulations. Existing deep-learning methods of dynamic contact prediction also lack specialized modeling for multidomain systems. Here, we present the Domain-Aware Residual Feature Modulation Network (DARMN), a deep learning framework for dynamic inter-residue contact prediction in MDP. Built on AlphaFold2 representations, DARMN uses coevolutionary information from multiple sequence alignments to capture sparse interdomain contact signals and applies Residual Feature-wise Linear Modulation to efficiently fuse single and pair representations. Furthermore, we design a domain-aware weighted focal loss function to distinguish between intradomain and interdomain contacts, thereby alleviating class imbalance and enhancing the learning of interdomain contacts. DARMN outperforms existing dynamic contact prediction and conformational ensemble prediction models, especially in long-distance contact identification, and generalizes well to unseen MDP. DARMN thus provides a useful computational framework for sequence design targeting conformational stabilization and mechanistic studies of MDP.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c00754","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T02:44:30Z","timestamp":1784256270000},"page":"7394-7406","source":"Crossref","is-referenced-by-count":0,"title":["DARMN: Domain-Aware\nResidual Feature Modulation Network\nfor Multidomain Protein Dynamic Inter-Residue Contact Prediction"],"prefix":"10.1021","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8239-2035","authenticated-orcid":true,"given":"Jing","family":"Xiao","sequence":"first","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, PR China, 310058"]},{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"National Engineering Center for New Vaccine Research , ,","place":["Beijing, PR China, 101111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei Bu","family":"Wang","sequence":"additional","affiliation":[{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"China National Biotec Group Company Limited , , ,","place":["Beijing, PR China, 100024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Bo","family":"Ma","sequence":"additional","affiliation":[{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"National Engineering Center for New Vaccine Research , ,","place":["Beijing, PR China, 101111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze Yuan","family":"Dong","sequence":"additional","affiliation":[{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"National Engineering Center for New Vaccine Research , ,","place":["Beijing, PR China, 101111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0363-7018","authenticated-orcid":true,"given":"Jiao","family":"Li","sequence":"additional","affiliation":[{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"National Engineering Center for New Vaccine Research , ,","place":["Beijing, PR China, 101111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Guo","family":"Su","sequence":"additional","affiliation":[{"name":"National Vaccine and Serum Institute (NVSI) , , ,","place":["Beijing, PR China, 101111"]},{"name":"National Engineering Center for New Vaccine Research , ,","place":["Beijing, PR China, 101111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2926-1864","authenticated-orcid":true,"given":"Jingyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, PR China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"issue":"1","key":"2026072808092151200_cit1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/S0006-3495(00)76602-1","article-title":"The thermal stability of immunoglobulin: unfolding and aggregation\nof a multi-domain protein","volume":"78","author":"Vermeer","year":"2000","journal-title":"Biophys. J."},{"issue":"5626","key":"2026072808092151200_cit2","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1126\/science.1085371","article-title":"Evolution\nof the protein repertoire","volume":"300","author":"Chothia","year":"2003","journal-title":"Science"},{"key":"2026072808092151200_cit3","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/s0022-2836(77)80200-3","article-title":"The Protein Data Bank:\na computer-based archival file\nfor macromolecular structures","volume":"112","author":"Bernstein","year":"1977","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026072808092151200_cit4","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.jmb.2005.02.007","article-title":"Multi-domain proteins\nin the three kingdoms of life:\norphan domains and other unassigned regions","volume":"348","author":"Ekman","year":"2005","journal-title":"J. Mol. Biol."},{"issue":"5","key":"2026072808092151200_cit5","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.jmb.2005.04.028","article-title":"Cooperative\nfolding\nin a multi-domain protein","volume":"349","author":"Batey","year":"2005","journal-title":"J. Mol. Biol."},{"issue":"11","key":"2026072808092151200_cit6","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.1038\/s41594-025-01676-5","article-title":"The human ribosome modulates multidomain protein\nbiogenesis by delaying cotranslational domain docking","volume":"32","author":"Pellowe","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026072808092151200_cit7","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1038\/s41467-026-69673-w","article-title":"Allosteric\nand energetic remodeling of a PDZ domain by protein domain extensions","volume":"17","author":"Hidalgo-Carcedo","year":"2026","journal-title":"Nat. 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Biol."},{"issue":"1","key":"2026072808092151200_cit26","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1038\/s41467-021-22089-0","article-title":"Hinge-shift\nmechanism as a protein design principle for the evolution of \u03b2-lactamases\nfrom substrate promiscuity to specificity","volume":"12","author":"Modi","year":"2021","journal-title":"Nat.\nCommun."},{"key":"2026072808092151200_cit27","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41467-025-66958-4","article-title":"Temporally\nresolved and interpretable machine learning model of GPCR conformational\ntransition","volume":"17","author":"Manookian","year":"2025","journal-title":"Nat. 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Theory Comput."},{"issue":"8","key":"2026072808092151200_cit30","doi-asserted-by":"publisher","first-page":"6253","DOI":"10.1039\/D2CP02890E","article-title":"Reconciling membrane\nprotein simulations\nwith experimental DEER spectroscopy data","volume":"25","author":"Mittal","year":"2023","journal-title":"Phys.\nChem. Chem. Phys."},{"key":"2026072808092151200_cit31","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.20.671365","article-title":"ESMDynamic: Fast and\nAccurate Prediction of Protein Dynamic Contact Maps from Single Sequences","author":"Kleiman","year":"2025","journal-title":"bioRxiv"},{"key":"2026072808092151200_cit32","doi-asserted-by":"publisher","DOI":"10.1126\/science.adv7953","article-title":"Computational design of conformation-biasing mutations\nto alter protein functions","volume":"391","author":"Cavanagh","year":"2026","journal-title":"Science"},{"key":"2026072808092151200_cit33","doi-asserted-by":"publisher","first-page":"102940","DOI":"10.1016\/j.sbi.2024.102940","article-title":"Engineering the native ensemble to\ntune protein function:\nDiverse mutational strategies and interlinked molecular mechanisms","volume":"89","author":"Kannan","year":"2024","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026072808092151200_cit34","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.pnmrs.2014.05.003","article-title":"NMR approaches for\nstructural analysis of multidomain proteins and complexes in solution","volume":"80","author":"Go\u0308bl","year":"2014","journal-title":"Prog. Nucl. Magn. Reson. Spectrosc."},{"issue":"9","key":"2026072808092151200_cit35","doi-asserted-by":"publisher","first-page":"10548","DOI":"10.3390\/molecules180910548","article-title":"Ensemble-based\ninterpretations of\nNMR structural data to describe protein internal dynamics","volume":"18","author":"A\u0301ngya\u0301n","year":"2013","journal-title":"Molecules"},{"issue":"34","key":"2026072808092151200_cit36","doi-asserted-by":"publisher","first-page":"10420","DOI":"10.1021\/ja030153x","article-title":"Cross-correlated\nrelaxation enhanced 1H\u2013 13C NMR spectroscopy of methyl groups\nin very high molecular weight proteins and protein complexes","volume":"125","author":"Tugarinov","year":"2003","journal-title":"J. Am. Chem. 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Model."},{"issue":"6761","key":"2026072808092151200_cit48","doi-asserted-by":"publisher","DOI":"10.1126\/science.adv9817","article-title":"Scalable emulation of protein equilibrium ensembles\nwith generative deep learning","volume":"389","author":"Lewis","year":"2025","journal-title":"Science"},{"key":"2026072808092151200_cit49","unstructured":"Jing, B.; Berger, B.; Jaakkola, T.\n          AlphaFold\nmeets\nflow matching for generating protein ensembles. In  Proceedings of the 41st International Conference on Machine Learning; JMLR.org, 2024."},{"issue":"6557","key":"2026072808092151200_cit50","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and\ninteractions using a three-track neural network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"issue":"6637","key":"2026072808092151200_cit51","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-scale prediction\nof atomic-level protein structure with\na language model","volume":"379","author":"Lin","year":"2023","journal-title":"Science"},{"issue":"2","key":"2026072808092151200_cit52","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/s41592-023-02130-4","article-title":"Improving deep learning protein monomer\nand complex structure prediction\nusing DeepMSA2 with huge metagenomics data","volume":"21","author":"Zheng","year":"2024","journal-title":"Nat. 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