{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:15:57Z","timestamp":1785161757553,"version":"3.55.0"},"reference-count":81,"publisher":"American Chemical Society (ACS)","issue":"14","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024QC184"],"award-info":[{"award-number":["ZR2024QC184"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2025MS470"],"award-info":[{"award-number":["ZR2025MS470"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China (973 Program)","doi-asserted-by":"crossref","award":["2025YFA0922303"],"award-info":[{"award-number":["2025YFA0922303"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"State Key Laboratory of Mechanical Transmission","award":["SKLMTFCP-2023-02"],"award-info":[{"award-number":["SKLMTFCP-2023-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A tightly packed hydrophobic core, with regions composed of hydrophobic residues defined as hydrophobic clusters, is a hallmark of globular proteins. However, quantitative rules governing the formation of stable hydrophobic clusters remain unclear. This is mainly due to the exponential growth in residue combinations with the number of sites in the clusters, which makes experimental characterization of all variants highly challenging. Current physics-based energy functions and deep learning models struggle with both accuracy and interpretability when modeling the stability of hydrophobic clusters. The advent of high-accuracy protein structure prediction models has enabled structural proteomics studies with hundreds of millions of structures. The triosephosphate isomerase (TIM) barrel, among the most abundant fold architectures, has been extensively investigated in evolutionary studies and protein design. In this study, we developed the hydrophobic packing fingerprints quantitative platform, qPacking, to define five hydrophobic packing descriptors (HPDs) for hydrophobic residues (A, V, I, L, and M) and to systematically quantify the hydrophobic clusters within TIM barrels. Hydrophobic clusters in TIM barrels were predominantly located in \u03b1\u2013\u03b2 regions rather than in \u03b2-barrel regions. Compared with their nonthermophilic counterparts, thermophilic TIM barrels exhibited larger and more densely packed hydrophobic clusters, with the most pronounced differences observed in the closure regions. Evolutionary analysis indicated that selection of residues within hydrophobic clusters involved a trade-off between packing area and spatial steric constraints. Feature analysis indicated that HPDs showed distributional differences between thermophilic and nonthermophilic TIM barrels. In summary, qPacking and HPDs provided a quantitative framework for understanding and optimizing protein thermal stability.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01179","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:12:03Z","timestamp":1783419123000},"page":"8087-8101","source":"Crossref","is-referenced-by-count":0,"title":["Structural Proteomics-Based\nDeciphering of Hydrophobic\nPacking Fingerprints Informing Protein Thermostability in TIM Barrels"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3682-8307","authenticated-orcid":true,"given":"Zhixin","family":"Dou","sequence":"first","affiliation":[{"name":"Shandong University , , No. 72 Binhai Road , ,","place":["Qingdao, P. R. China, 266237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5287-5218","authenticated-orcid":true,"given":"Xiuyun","family":"Wu","sequence":"additional","affiliation":[{"name":"Shandong University , , No. 72 Binhai Road , ,","place":["Qingdao, P. R. China, 266237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wan","sequence":"additional","affiliation":[{"name":"Shandong University , , Shunhua Road , ,","place":["Jinan, P. R. China, 250101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gong","sequence":"additional","affiliation":[{"name":"Shandong University , , Shunhua Road , ,","place":["Jinan, P. R. China, 250101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8159-6886","authenticated-orcid":true,"given":"Lushan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong University , , No. 72 Binhai Road , ,","place":["Qingdao, P. R. China, 266237"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"issue":"5","key":"2026072709091390400_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.70045","article-title":"Computation\nof Protein Thermostability and Epistasis","volume":"15","author":"Peccati","year":"2025","journal-title":"WIREs\nComput. Mol. Sci."},{"issue":"6968","key":"2026072709091390400_cit2","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1038\/nature02261","article-title":"Protein\nFolding and Misfolding","volume":"426","author":"Dobson","year":"2003","journal-title":"Nature"},{"issue":"3","key":"2026072709091390400_cit3","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1002\/pro.2860","article-title":"Clusters of Isoleucine,\nLeucine, and Valine Side Chains\nDefine Cores of Stability in High-energy States of Globular Proteins:\nSequence Determinants of Structure and Stability","volume":"25","author":"Kathuria","year":"2016","journal-title":"Protein Sci."},{"issue":"4948","key":"2026072709091390400_cit4","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1126\/science.2315699","article-title":"Deciphering the\nMessage in Protein Sequences: Tolerance to Amino Acid Substitutions","volume":"247","author":"Bowie","year":"1990","journal-title":"Science"},{"issue":"W1","key":"2026072709091390400_cit5","doi-asserted-by":"publisher","first-page":"W559","DOI":"10.1093\/nar\/gkab375","article-title":"ProteinTools:\nA Toolkit to Analyze\nProtein Structures","volume":"49","author":"Ferruz","year":"2021","journal-title":"Nucleic Acids Res."},{"issue":"7973","key":"2026072709091390400_cit6","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-023-06328-6","article-title":"Mega-Scale Experimental\nAnalysis of Protein Folding\nStability in Biology and Design","volume":"620","author":"Tsuboyama","year":"2023","journal-title":"Nature"},{"issue":"33","key":"2026072709091390400_cit7","doi-asserted-by":"publisher","first-page":"16367","DOI":"10.1073\/pnas.1903888116","article-title":"Protein Stability\nEngineering Insights Revealed by Domain-Wide Comprehensive Mutagenesis","volume":"116","author":"Nisthal","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"8035","key":"2026072709091390400_cit8","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1038\/s41586-024-07966-0","article-title":"The Genetic Architecture of Protein Stability","volume":"634","author":"Faure","year":"2024","journal-title":"Nature"},{"issue":"2","key":"2026072709091390400_cit9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110207","article-title":"Predicting and Interpreting\nLarge-Scale Mutagenesis Data Using Analyses\nof Protein Stability and Conservation","volume":"38","author":"H\u00f8ie","year":"2022","journal-title":"Cell\nRep."},{"issue":"12","key":"2026072709091390400_cit10","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s44222-025-00349-8","article-title":"AI-Driven Protein Design","volume":"3","author":"Koh","year":"2025","journal-title":"Nat.\nRev. Bioeng."},{"issue":"18","key":"2026072709091390400_cit11","doi-asserted-by":"publisher","first-page":"14085","DOI":"10.1021\/acs.chemrev.1c00757","article-title":"Protein Design:\nFrom the Aspect of Water Solubility and Stability","volume":"122","author":"Qing","year":"2022","journal-title":"Chem. Rev."},{"issue":"3","key":"2026072709091390400_cit12","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.cell.2023.12.028","article-title":"De Novo Protein\nDesign\u2500From New Structures to Programmable Functions","volume":"187","author":"Kortemme","year":"2024","journal-title":"Cell"},{"issue":"2","key":"2026072709091390400_cit13","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.cell.2012.03.016","article-title":"Role of the Biomolecular Energy Gap\nin Protein Design, Structure,\nand Evolution","volume":"149","author":"Fleishman","year":"2012","journal-title":"Cell"},{"issue":"11","key":"2026072709091390400_cit14","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.cels.2023.10.006","article-title":"A New Age in Protein\nDesign Empowered by Deep Learning","volume":"14","author":"Khakzad","year":"2023","journal-title":"Cell Syst."},{"key":"2026072709091390400_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2024.108495","article-title":"Interpretable and\nExplainable Predictive Machine Learning Models for Data-Driven Protein\nEngineering","volume":"79","author":"Medina-Ortiz","year":"2025","journal-title":"Biotechnol. Adv."},{"issue":"6","key":"2026072709091390400_cit16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1145\/3715318","article-title":"Scientific\nLarge Language Models: A Survey on Biological & Chemical Domains","volume":"57","author":"Zhang","year":"2025","journal-title":"ACM Comput. Surv"},{"issue":"10","key":"2026072709091390400_cit17","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2025.101065","article-title":"State-of-the-Art and Future Directions in Structural\nProteomics","volume":"24","author":"Happonen","year":"2025","journal-title":"Mol. Cell. Proteomics"},{"issue":"8016","key":"2026072709091390400_cit18","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure\nPrediction of\nBiomolecular Interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"issue":"6637","key":"2026072709091390400_cit19","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-Scale Prediction of Atomic-Level Protein Structure with\na Language Model","volume":"379","author":"Lin","year":"2023","journal-title":"Science"},{"issue":"6557","key":"2026072709091390400_cit20","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate Prediction\nof Protein Structures and Interactions Using a Three-Track Neural\nNetwork","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"2026072709091390400_cit21","doi-asserted-by":"crossref","unstructured":"Method of the\nYear 2021: Protein Structure Prediction\n          Nat.\nMethods\n          2022; Vol. 19(1), , pp 1\u2013110.1038\/s41592-021-01380-4.","DOI":"10.1038\/s41592-021-01380-4"},{"issue":"9","key":"2026072709091390400_cit22","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.tibs.2010.04.007","article-title":"When Proteomics\nMeets Structural Biology","volume":"35","author":"Zhou","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"2026072709091390400_cit23","doi-asserted-by":"publisher","DOI":"10.1016\/j.biortech.2023.129664","article-title":"Multi-Omics\nStudy of Sulfur Metabolism Affecting Functional Microbial Community\nSuccession during Aerobic Solid-State Fermentation","volume":"387","author":"Zhang","year":"2023","journal-title":"Bioresour. Technol."},{"issue":"3","key":"2026072709091390400_cit24","doi-asserted-by":"publisher","DOI":"10.1103\/PRXLife.2.033011","article-title":"Proteome-Wide\nAssessment of Protein Structural Perturbations under High Pressure","volume":"2","author":"Moran","year":"2024","journal-title":"PRX Life"},{"issue":"20","key":"2026072709091390400_cit25","doi-asserted-by":"publisher","first-page":"7885","DOI":"10.1021\/acs.jcim.4c01303","article-title":"qProtein:\nExploring\nPhysical Features of Protein Thermostability Based on Structural Proteomics","volume":"64","author":"Dou","year":"2024","journal-title":"J. Chem. Inf. Model."},{"issue":"7","key":"2026072709091390400_cit26","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msae127","article-title":"Deciphering Structural Traits for Thermal and Kinetic\nStability across Protein Family Evolution through Ancestral Sequence\nReconstruction","volume":"41","author":"Cea","year":"2024","journal-title":"Mol. Biol. Evol."},{"issue":"D1","key":"2026072709091390400_cit27","doi-asserted-by":"publisher","first-page":"D348","DOI":"10.1093\/nar\/gkae1087","article-title":"CATH v4.4: Major Expansion\nof CATH\nby Experimental and Predicted Structural Data","volume":"53","author":"Waman","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"2026072709091390400_cit28","doi-asserted-by":"publisher","DOI":"10.1126\/science.adq4946","article-title":"Exploring Structural\nDiversity across the Protein Universe with The Encyclopedia of Domains","volume":"386","author":"Lau","year":"2024","journal-title":"Science"},{"issue":"1","key":"2026072709091390400_cit29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/nchembio.1966","article-title":"De Novo Design of a Four-Fold Symmetric\nTIM-Barrel Protein with Atomic-Level Accuracy","volume":"12","author":"Huang","year":"2016","journal-title":"Nat. Chem. Biol."},{"issue":"11","key":"2026072709091390400_cit30","doi-asserted-by":"publisher","first-page":"4038","DOI":"10.1021\/cr030191z","article-title":"Catalytic Versatility, Stability, and Evolution of\nthe (\u0392\u03b1)8 -Barrel Enzyme Fold","volume":"105","author":"Sterner","year":"2005","journal-title":"Chem. Rev."},{"issue":"17","key":"2026072709091390400_cit31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2019571118","article-title":"A Conserved\nFolding Nucleus Sculpts the Free Energy\nLandscape of Bacterial and Archaeal Orthologs from a Divergent TIM\nBarrel Family","volume":"118","author":"Jain","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"18","key":"2026072709091390400_cit32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167153","article-title":"The Stability Landscape of de Novo TIM Barrels Explored by a Modular Design Approach","volume":"433","author":"Romero-Romero","year":"2021","journal-title":"J. Mol. Biol."},{"issue":"15","key":"2026072709091390400_cit33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.168967","article-title":"AlphaFold Protein Structure\nDatabase and 3D-Beacons: New Data and Capabilities","volume":"437","author":"Fleming","year":"2025","journal-title":"J. Mol. Biol."},{"key":"2026072709091390400_cit34","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.17456.1","article-title":"Pdb-Tools:\nA Swiss Army Knife for Molecular Structures","volume":"7","author":"Rodrigues","year":"2018","journal-title":"F1000Research"},{"issue":"8","key":"2026072709091390400_cit35","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70208","article-title":"DSSP 4: FAIR Annotation\nof Protein Secondary Structure","volume":"34","author":"Hekkelman","year":"2025","journal-title":"Protein Sci."},{"issue":"6533","key":"2026072709091390400_cit36","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay2784","article-title":"Parallel Molecular\nMechanisms for\nEnzyme Temperature Adaptation","volume":"371","author":"Pinney","year":"2021","journal-title":"Science"},{"issue":"1","key":"2026072709091390400_cit37","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-018-1320-7","article-title":"Correlating\nEnzyme Annotations with a Large Set of Microbial Growth Temperatures\nReveals Metabolic Adaptations to Growth at Diverse Temperatures","volume":"18","author":"Engqvist","year":"2018","journal-title":"BMC Microbiol."},{"issue":"10","key":"2026072709091390400_cit38","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1002\/pro.3698","article-title":"Methionine\nin Proteins: The Cinderella of the Proteinogenic Amino Acids","volume":"28","author":"Aledo","year":"2019","journal-title":"Protein Sci."},{"issue":"4","key":"2026072709091390400_cit39","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.ijbiomac.2011.01.008","article-title":"Aromatic\u2013Aromatic\nInteractions\nDatabase, A2ID: An Analysis of Aromatic \u03c0-Networks\nin Proteins","volume":"48","author":"Chourasia","year":"2011","journal-title":"Int. J. Biol. Macromol."},{"issue":"45","key":"2026072709091390400_cit40","doi-asserted-by":"publisher","first-page":"24836","DOI":"10.1021\/jacs.3c09198","article-title":"The Energetic Origins of Pi\u2013Pi Contacts in Proteins","volume":"145","author":"Carter-Fenk","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026072709091390400_cit41","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/j.csbj.2022.04.025","article-title":"Contribution\nof Hydrophobic Interactions to Protein\nMechanical Stability","volume":"20","author":"Ferenczy","year":"2022","journal-title":"Comput. Struct. Biotechnol.\nJ."},{"issue":"11","key":"2026072709091390400_cit42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080635","article-title":"Maximum\nAllowed Solvent Accessibilites of Residues in Proteins","volume":"8","author":"Tien","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"2026072709091390400_cit43","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1080\/00018730601170527","article-title":"Characterization\nof Complex Networks: A Survey of Measurements","volume":"56","author":"da F. Costa","year":"2007","journal-title":"Adv. Phys."},{"issue":"4","key":"2026072709091390400_cit44","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1006\/jmbi.1998.1645","article-title":"Contact Order, Transition\nState Placement\nand the Refolding Rates of Single Domain Proteins1","volume":"277","author":"Plaxco","year":"1998","journal-title":"J. Mol. Biol."},{"issue":"47","key":"2026072709091390400_cit45","doi-asserted-by":"publisher","first-page":"14605","DOI":"10.1073\/pnas.1510748112","article-title":"Designed Protein\nReveals Structural Determinants of Extreme Kinetic Stability","volume":"112","author":"Broom","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"49","key":"2026072709091390400_cit46","doi-asserted-by":"publisher","first-page":"11450","DOI":"10.1021\/acs.jpcb.8b07379","article-title":"Stability Effects of\nProtein Mutations: The Role of Long-Range Contacts","volume":"122","author":"Bigman","year":"2018","journal-title":"J. Phys. Chem. B"},{"issue":"1","key":"2026072709091390400_cit47","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/S0301-4622(99)00010-1","article-title":"Importance of Long-Range\nInteractions in Protein Folding","volume":"77","author":"Gromiha","year":"1999","journal-title":"Biophys. Chem."},{"key":"2026072709091390400_cit48","doi-asserted-by":"publisher","first-page":"2354","DOI":"10.1007\/978-1-4419-9863-7_1185","article-title":"Wilcoxon Rank\nSum Test","volume-title":"Encyclopedia of Systems Biology","author":"Haynes","year":"2013"},{"key":"2026072709091390400_cit49","doi-asserted-by":"publisher","DOI":"10.1051\/itmconf\/20182300037","article-title":"Kernel Density\nEstimation and Its Application","volume":"23","author":"We\u0328glarczyk","year":"2018","journal-title":"ITM Web Conf."},{"issue":"3","key":"2026072709091390400_cit50","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: Fundamental Algorithms\nfor Scientific Computing in Python","volume":"17","author":"Virtanen","year":"2020","journal-title":"Nat. Methods"},{"key":"2026072709091390400_cit51","doi-asserted-by":"publisher","first-page":"56","DOI":"10.25080\/Majora-92bf1922-00a","volume-title":"Data Structures for Statistical\nComputing","author":"McKinney","year":"2010"},{"issue":"9","key":"2026072709091390400_cit52","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1038\/s41592-022-01585-1","article-title":"US-Align: Universal\nStructure Alignments of Proteins, Nucleic Acids, and Macromolecular\nComplexes","volume":"19","author":"Zhang","year":"2022","journal-title":"Nat. Methods"},{"issue":"3","key":"2026072709091390400_cit53","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/s41592-025-02593-7","article-title":"Rapid and\nSensitive Protein Complex Alignment with Foldseek-Multimer","volume":"22","author":"Kim","year":"2025","journal-title":"Nat. Methods"},{"issue":"D1","key":"2026072709091390400_cit54","doi-asserted-by":"publisher","first-page":"D490","DOI":"10.1093\/nar\/gks1211","article-title":"New Functional Families\n(FunFams) in CATH to Improve the Mapping of Conserved Functional Sites\nto 3D Structures","volume":"41","author":"Sillitoe","year":"2012","journal-title":"Nucleic Acids Res."},{"issue":"10","key":"2026072709091390400_cit55","doi-asserted-by":"publisher","first-page":"3338","DOI":"10.1073\/pnas.85.10.3338","article-title":"Structural\nPrinciples of Parallel Beta-Barrels in Proteins","volume":"85","author":"Lasters","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"4","key":"2026072709091390400_cit56","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1007\/s00894-010-0784-7","article-title":"Allosteric Transition and Binding\nof Small Molecule Effectors Causes Curvature Change in Central \u03b2-Sheets\nof Selected Enzymes","volume":"17","author":"Tolonen","year":"2011","journal-title":"J. Mol. Model."},{"key":"2026072709091390400_cit57","doi-asserted-by":"publisher","DOI":"10.34133\/2022\/9842315","article-title":"De Novo\nDesign of a Highly Stable Ovoid TIM Barrel: Unlocking Pocket Shape\ntowards Functional Design","volume":"2022","author":"Chu","year":"2022","journal-title":"BioDesign Res."},{"key":"2026072709091390400_cit58","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.sbi.2020.12.007","article-title":"Evolution,\nFolding, and Design of TIM Barrels and Related Proteins","volume":"68","author":"Romero-Romero","year":"2021","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026072709091390400_cit59","doi-asserted-by":"crossref","unstructured":"Jalan, A. A.; Hassine, L.; Romero-Romero, S.; Hu\u0308bner, J.; Schweimer, K.; Ho\u0308cker, B.\n          Hydrophobic Clusters\nDirect Folding of a Synthetic Chimeric Protein\n          bioRxiv\n          2023\n          10.1101\/2023.09.29.560087.","DOI":"10.1101\/2023.09.29.560087"},{"key":"2026072709091390400_cit60","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2025.07.013","article-title":"Hydrophobic Cluster\nAnalysis at Protein and Proteome\nScales","volume":"239","author":"Callebaut","year":"2025","journal-title":"Biochimie"},{"issue":"1","key":"2026072709091390400_cit61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14614","article-title":"Correlation of Fitness\nLandscapes from Three Orthologous TIM Barrels Originates from Sequence\nand Structure Constraints","volume":"8","author":"Chan","year":"2017","journal-title":"Nat. Commun."},{"issue":"9","key":"2026072709091390400_cit62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007179","article-title":"\u0392\u03b1-Hairpin\nClamps Brace \u0392\u03b1\u03b2 Modules and Can Make Substantive\nContributions to the Stability of TIM Barrel Proteins","volume":"4","author":"Yang","year":"2009","journal-title":"PLoS One"},{"issue":"5","key":"2026072709091390400_cit63","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1016\/j.jmb.2009.12.048","article-title":"Desolvation and Development of Specific\nHydrophobic\nCore Packing during Im7 Folding","volume":"396","author":"Bartlett","year":"2010","journal-title":"J. Mol. Biol."},{"issue":"4","key":"2026072709091390400_cit64","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1002\/(SICI)1097-0134(19990901)36:4%3C436:AID-PROT7%3E3.0.CO;2-L","article-title":"Effects of core-packing on the structure,\nfunction, and mechanics of a four-helix-bundle protein ROP","volume":"36","author":"Ceruso","year":"1999","journal-title":"Proteins:Struct., Funct., Genet."},{"issue":"6758","key":"2026072709091390400_cit65","doi-asserted-by":"publisher","DOI":"10.1126\/science.adq3948","article-title":"Genetics, Energetics,\nand Allostery in Proteins with Randomized Cores and Surfaces","volume":"389","author":"Escobedo","year":"2025","journal-title":"Science"},{"issue":"1","key":"2026072709091390400_cit66","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/bmsp.12006","article-title":"Sample Size Determinations\nfor Welch\u2019s Test in One-Way Heteroscedastic\nANOVA","volume":"67","author":"Jan","year":"2014","journal-title":"Br. J. Math. Stat. Psychol."},{"issue":"2","key":"2026072709091390400_cit67","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nrg.2015.18","article-title":"Causes\nof Evolutionary Rate Variation\namong Protein Sites","volume":"17","author":"Echave","year":"2016","journal-title":"Nat. Rev. Genet."},{"issue":"1","key":"2026072709091390400_cit68","doi-asserted-by":"publisher","DOI":"10.1186\/s12858-015-0047-4","article-title":"Design of Symmetric TIM Barrel Proteins\nfrom First Principles","volume":"16","author":"Nagarajan","year":"2015","journal-title":"BMC Biochem."},{"issue":"24","key":"2026072709091390400_cit69","doi-asserted-by":"publisher","first-page":"9026","DOI":"10.1039\/C8CS00014J","article-title":"Engineering\nMore Stable Proteins","volume":"47","author":"Kazlauskas","year":"2018","journal-title":"Chem. Soc. Rev."},{"issue":"1","key":"2026072709091390400_cit70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-68979-z","article-title":"Protein\nC-Terminal Variations Impact Proteostasis","volume":"17","author":"Chu","year":"2026","journal-title":"Nat.\nCommun."},{"key":"2026072709091390400_cit71","doi-asserted-by":"publisher","DOI":"10.5936\/csbj.201209014","article-title":"Emerging Role of\nN- and C-Terminal Interactions in\nStabilizing (\u03b2\/\u03b1)8 Fold with Special Emphasis on Family\n10 Xylanases","volume":"2","author":"Bhardwaj","year":"2012","journal-title":"Comput. Struct. Biotechnol. J."},{"issue":"18","key":"2026072709091390400_cit72","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1111\/febs.13355","article-title":"Structural\nInsights into N-terminal to C-terminal Interactions and Implications\nfor Thermostability of a (\u03b2\/\u03b1)8 -triosephosphate\nIsomerase Barrel Enzyme","volume":"282","author":"Mahanta","year":"2015","journal-title":"FEBS J."},{"issue":"1","key":"2026072709091390400_cit73","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-142","article-title":"Role of Long- and Short-Range\nHydrophobic, Hydrophilic and Charged\nResidues Contact Network in Protein\u2019s Structural Organization","volume":"13","author":"Sengupta","year":"2012","journal-title":"BMC Bioinf."},{"issue":"6","key":"2026072709091390400_cit74","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1080\/07391102.2012.689696","article-title":"A Rigid\nNetwork\nof Long-Range Contacts Increases Thermostability in a Mutant Endoglucanase","volume":"30","author":"Rader","year":"2012","journal-title":"J. Biomol. Struct. Dyn."},{"issue":"1","key":"2026072709091390400_cit75","doi-asserted-by":"publisher","DOI":"10.1186\/s13068-023-02411-2","article-title":"Dynamics of Loops Surrounding the\nActive Site Architecture in GH5_2\nSubfamily TfCel5A for Cellulose Degradation","volume":"16","author":"Wu","year":"2023","journal-title":"Biotechnol. Biofuels Bioprod."},{"issue":"6434","key":"2026072709091390400_cit76","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1126\/science.aav7541","article-title":"Packing\nof Apolar Side Chains Enables Accurate Design\nof Highly Stable Membrane Proteins","volume":"363","author":"Mravic","year":"2019","journal-title":"Science"},{"issue":"31","key":"2026072709091390400_cit77","doi-asserted-by":"publisher","first-page":"21340","DOI":"10.1039\/C6CP02998A","article-title":"Structural and Dynamic Evolution\nof the Amphipathic N-Terminus Diversifies Enzyme Thermostability in\nthe Glycoside Hydrolase Family 12","volume":"18","author":"Jiang","year":"2016","journal-title":"Phys. Chem.\nChem. Phys."},{"issue":"7910","key":"2026072709091390400_cit78","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/s41586-022-04654-9","article-title":"Design of Protein-Binding Proteins from the Target Structure Alone","volume":"605","author":"Cao","year":"2022","journal-title":"Nature"},{"issue":"12","key":"2026072709091390400_cit79","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70360","article-title":"Structure-Guided Engineering\nof Protein\nStability through Core Hydrophobicity","volume":"34","author":"Ravichandran","year":"2025","journal-title":"Protein\nSci."},{"key":"2026072709091390400_cit80","doi-asserted-by":"publisher","DOI":"10.1017\/S0033583524000131","article-title":"Atomic Molecular Dynamics Simulation\nAdvances of de Novo-Designed Proteins","volume":"57","author":"Wang","year":"2024","journal-title":"Q. Rev.\nBiophys."},{"issue":"49","key":"2026072709091390400_cit81","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2309884120","article-title":"MEnTaT: A Machine-Learning Approach\nfor the Identification of Mutations to Increase Protein Stability","volume":"120","author":"Muellers","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c01179","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/14\/8087\/65809907\/acs.jcim.6c01179.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/14\/8087\/65809907\/acs.jcim.6c01179.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:32:26Z","timestamp":1785159146000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/14\/8087\/5202429\/Structural-Proteomics-Based-Deciphering-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":81,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7,7]]},"published-print":{"date-parts":[[2026,7,27]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c01179","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}