{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T03:19:09Z","timestamp":1787541549777,"version":"build-2736575974"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>The emergence of foundation models with trillion-level parameters has redefined the landscape of artificial intelligence. Various fields are developing their own large-scale models, which can solve many problems within the field and improve work efficiency. Biological large-scale models are a cross-disciplinary research field that combines mathematics, computer science, and biology, aiming to simulate and understand the structure, function, and dynamic changes of biological systems through the establishment of complex computational models. This field covers multiple levels such as biological pathways, population dynamics, protein folding, etc., providing us with tools for deep exploration of the mysteries of life and applications in medicine, ecology, and other fields. This article reviews the background and research status of biological large-scale models, and discusses future directions. Large language models (LLMs) and other large-scale foundation models have rapidly advanced in recent years, enabling powerful representation learning and generation across text, sequences, and multimodal data. In bioinformatics and biomedicine, these models are increasingly used to analyze genomic sequences, infer protein properties and structures, support drug discovery, and integrate heterogeneous biomedical evidence. This survey reviews the basic principles of LLMs and summarizes representative applications in (i) gene and genome sequence analysis, (ii) protein structure and function prediction, and (iii) drug design, including virtual screening and personalized medicine. We also discuss emerging multi-model modeling approaches, as well as key challenges such as data quality and privacy, interpretability, generalization to new organisms and tasks, and responsible deployment in health-related settings. Finally, we outline future directions for developing reliable, scalable, and explainable bioinformatics foundation models.<\/jats:p>","DOI":"10.3389\/fgene.2026.1797863","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:24:57Z","timestamp":1787538297000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Large language models in bioinformatics: a comprehensive survey"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhigang","family":"Meng","sequence":"first","affiliation":[{"name":"School of Computer Science and Engineering, Changsha University","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikai","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Changsha University","place":["Changsha, China"]},{"name":"Department of Computer Science, College of Computer, Hunan University of Technology","place":["Zhuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Big Data Service and Management, School of Economics and Management, Changsha Normal University","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhen","family":"Xu","sequence":"additional","affiliation":[{"name":"Shantou University Medical College","place":["Shantou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3031","DOI":"10.1021\/acs.jctc.7b00125","article-title":"The Rosetta all-atom energy function for macromolecular modeling and design","volume":"13","author":"Alford","year":"2017","journal-title":"JCTC"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1038\/s41592-021-01252-x","article-title":"Effective gene expression prediction from sequence","volume":"18","author":"Avsec","year":"2021","journal-title":"Nat. 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