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The stability of these proteins is governed by both thermodynamic and kinetic factors that affect the folding\u2013unfolding equilibrium and the rate of irreversible denaturation. Structural studies have shown that enhanced thermostability often results from multiple cooperative interactions, including improved hydrophobic packing, strengthened electrostatic interactions, and optimized hydrogen\u2010bonding networks. Comparative studies between thermophilic and mesophilic proteins have helped to identify general mechanisms that support thermal adaptations. Mutational and protein\u2010engineering approaches have further demonstrated the influence of specific amino acid residues or motifs on the stability through altered or modified local structural interactions. In recent years, computational approaches and machine learning methods have emerged as inevitable tools to predict protein stability. Although these approaches have improved the predictions, there still exist several limitations like limited training datasets, bias toward certain protein families, difficulties in model interpretation, etc. Therefore, combining experimental thermodynamic data, structural studies, and modern AI\u2010based computational tools, it is possible to develop more reliable strategies to design thermostable proteins, in particular, for various industrial and biotechnological applications.<\/jats:p>","DOI":"10.1002\/open.70234","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T10:28:13Z","timestamp":1783938493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Adaptations of Thermophilic Proteins\u2014From Mechanistic Understanding to Machine Learning Approaches"],"prefix":"10.1002","volume":"15","author":[{"given":"Sermarajan","family":"Arunachalam","sequence":"first","affiliation":[{"name":"Department of Chemistry School of Advanced Sciences, Vellore Institute of Technology  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-9950","authenticated-orcid":false,"given":"Balamurali","family":"MM","sequence":"additional","affiliation":[{"name":"Centre for Healthcare Advancement, Innovation and Research Vellore Institute of Technology  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6410-7101","authenticated-orcid":false,"given":"Ramachandran","family":"Gnanasekaran","sequence":"additional","affiliation":[{"name":"Department of Chemistry School of Advanced Sciences, Vellore Institute of Technology  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"e_1_2_19_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119525899.ch14"},{"key":"e_1_2_19_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4CC03114H"},{"key":"e_1_2_19_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micres.2022.127115"},{"key":"e_1_2_19_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/chemengineering6040051"},{"key":"e_1_2_19_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.02.210"},{"key":"e_1_2_19_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.1c00512"},{"key":"e_1_2_19_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.826071"},{"key":"e_1_2_19_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biortech.2020.124558"},{"key":"e_1_2_19_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2021.08.024"},{"key":"e_1_2_19_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.870083"},{"key":"e_1_2_19_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(18)91704\u20107"},{"key":"e_1_2_19_13_1","first-page":"83","volume-title":"Advances in Microbial Physiology","author":"Farrell J.","year":"1969"},{"key":"e_1_2_19_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.169.3952.1316"},{"key":"e_1_2_19_15_1","doi-asserted-by":"publisher","DOI":"10.1515\/zpch\u20101927\u201013055"},{"key":"e_1_2_19_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/br.17.2.125-173.1953"},{"key":"e_1_2_19_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00869a032"},{"key":"e_1_2_19_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00408082"},{"key":"e_1_2_19_19_1","volume-title":"Thermophilic Microorganisms and Life at High Temperatures","author":"Brock T. 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