{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:02:18Z","timestamp":1789603338149,"version":"build-2803163510"},"reference-count":100,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000104","name":"NASA","doi-asserted-by":"publisher","award":["80NSSC25K7873"],"award-info":[{"award-number":["80NSSC25K7873"]}],"id":[{"id":"10.13039\/100000104","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut and Alice Wallenberg Foundation","doi-asserted-by":"publisher","award":["2019.0431"],"award-info":[{"award-number":["2019.0431"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000854","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["RGEC29\/2025"],"award-info":[{"award-number":["RGEC29\/2025"]}],"id":[{"id":"10.13039\/501100000854","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Trends in Chemistry"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1016\/j.trechm.2026.03.001","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T15:17:48Z","timestamp":1776352668000},"page":"362-376","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["The borderlands of foldability: lessons from simplified proteins"],"prefix":"10.1016","volume":"8","author":[{"given":"Koh","family":"Seya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfie-Louise R.","family":"Brownless","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shina C.L.","family":"Kamerlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam M.","family":"Longo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.trechm.2026.03.001_bb0005","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1038\/s41559-024-02461-1","article-title":"The nature of the last universal common ancestor and its impact on the early Earth system","volume":"8","author":"Moody","year":"2024","journal-title":"Nat. Ecol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0010","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.1021\/acs.chemrev.9b00664","article-title":"Prebiotic peptides: molecular hubs in the origin of life","volume":"120","author":"Frenkel-Pinter","year":"2020","journal-title":"Chem. Rev."},{"key":"10.1016\/j.trechm.2026.03.001_bb0015","doi-asserted-by":"crossref","first-page":"4442","DOI":"10.1073\/pnas.0501049102","article-title":"A mechanism for the association of amino acids with their codons and the origin of the genetic code","volume":"102","author":"Copley","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0020","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/0022-2836(68)90392-6","article-title":"The origin of the genetic code","volume":"38","author":"Crick","year":"1968","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0025","doi-asserted-by":"crossref","first-page":"11962","DOI":"10.1021\/acs.chemrev.4c00275","article-title":"Genetic code expansion history and modern innovations","volume":"124","author":"Costello","year":"2024","journal-title":"Chem. Rev."},{"key":"10.1016\/j.trechm.2026.03.001_bb0030","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1073\/pnas.72.5.1909","article-title":"A co-evolution theory of the genetic code","volume":"72","author":"Wong","year":"1975","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0035","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s11084-008-9150-5","article-title":"Which amino acids should be used in prebiotic chemistry studies?","volume":"38","author":"Zaia","year":"2008","journal-title":"Orig. Life Evol. Biosph."},{"key":"10.1016\/j.trechm.2026.03.001_bb0040","doi-asserted-by":"crossref","first-page":"823","DOI":"10.26464\/epp2024066","article-title":"Discharge plasma for prebiotic chemistry: pathways to life\u2019s building blocks","volume":"8","author":"Gan","year":"2024","journal-title":"Earth Planet. Phys."},{"key":"10.1016\/j.trechm.2026.03.001_bb0045","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1073\/pnas.1219530110","article-title":"Simplified protein design biased for prebiotic amino acids yields a foldable, halophilic protein","volume":"110","author":"Longo","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0050","doi-asserted-by":"crossref","first-page":"4456","DOI":"10.1021\/acs.biochem.0c00800","article-title":"Polyamines mediate folding of primordial hyperacidic helical proteins","volume":"59","author":"Despotovi\u0107","year":"2020","journal-title":"Biochemistry"},{"key":"10.1016\/j.trechm.2026.03.001_bb0055","doi-asserted-by":"crossref","DOI":"10.1093\/molbev\/msac032","article-title":"In vitro evolution reveals noncationic protein-RNA interaction mediated by metal ions","volume":"39","author":"Giacobelli","year":"2022","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0060","article-title":"Ancient amino acid sets enable stable protein folds","author":"Giacobelli","year":"2025","journal-title":"bioRxiv"},{"key":"10.1016\/j.trechm.2026.03.001_bb0065","doi-asserted-by":"crossref","first-page":"15731","DOI":"10.1073\/pnas.2001989117","article-title":"Primordial emergence of a nucleic acid-binding protein via phase separation and statistical ornithine-to-arginine conversion","volume":"117","author":"Longo","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0070","doi-asserted-by":"crossref","first-page":"11210","DOI":"10.1021\/jacs.8b07553","article-title":"Minimal heterochiral de novo designed 4Fe-4S binding peptide capable of robust electron transfer","volume":"140","author":"Kim","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.trechm.2026.03.001_bb0075","doi-asserted-by":"crossref","DOI":"10.1002\/pro.70273","article-title":"RNA binding and coacervation promote preservation of peptide form and function across the heterochiral\u2013homochiral divide","volume":"34","author":"Seal","year":"2025","journal-title":"Protein Sci."},{"key":"10.1016\/j.trechm.2026.03.001_bb0080","doi-asserted-by":"crossref","DOI":"10.1002\/anie.202505188","article-title":"Functional ambidexterity of an ancient nucleic acid-binding domain","volume":"64","author":"Weil-Ktorza","year":"2025","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"10.1016\/j.trechm.2026.03.001_bb0085","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.abb.2012.06.009","article-title":"Protein design at the interface of the pre-biotic and biotic worlds","volume":"526","author":"Longo","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"10.1016\/j.trechm.2026.03.001_bb0090","doi-asserted-by":"crossref","first-page":"D411","DOI":"10.1093\/nar\/gkae1029","article-title":"ECOD: integrating classifications of protein domains from experimental and predicted structures","volume":"53","author":"Schaeffer","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.trechm.2026.03.001_bb0095","doi-asserted-by":"crossref","first-page":"31149","DOI":"10.1073\/pnas.2002120117","article-title":"Robust folding of a de novo designed ideal protein even with most of the core mutated to valine","volume":"117","author":"Koga","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0100","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1073\/pnas.1015032108","article-title":"Experimental support for the evolution of symmetric protein architecture from a simple peptide motif","volume":"108","author":"Lee","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0105","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cell.2015.12.024","article-title":"De novo evolutionary emergence of a symmetrical protein is shaped by folding constraints","volume":"164","author":"Smock","year":"2016","journal-title":"Cell"},{"key":"10.1016\/j.trechm.2026.03.001_bb0110","doi-asserted-by":"crossref","first-page":"5414","DOI":"10.1021\/jacsau.5c00863","article-title":"Designing peptide fossils that model the evolution of the bacterial ferredoxin fold","volume":"5","author":"Jagilinki","year":"2025","journal-title":"JACS Au"},{"key":"10.1016\/j.trechm.2026.03.001_bb0115","doi-asserted-by":"crossref","first-page":"14150","DOI":"10.1021\/jacs.2c03819","article-title":"Peptide-RNA coacervates as a cradle for the evolution of folded domains","volume":"144","author":"Seal","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.trechm.2026.03.001_bb0120","doi-asserted-by":"crossref","first-page":"5938","DOI":"10.1038\/s41467-024-50013-9","article-title":"An ancestral fold reveals the evolutionary link between RNA polymerase and ribosomal proteins","volume":"15","author":"Yagi","year":"2024","journal-title":"Nat. Commun."},{"key":"10.1016\/j.trechm.2026.03.001_bb0125","doi-asserted-by":"crossref","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":"10.1016\/j.trechm.2026.03.001_bb0130","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1126\/science.152.3720.363","article-title":"Evolution of the structure of ferredoxin based on living relics of primitive amino acid sequences","volume":"152","author":"Eck","year":"1966","journal-title":"Science"},{"key":"10.1016\/j.trechm.2026.03.001_bb0135","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.sbi.2015.05.004","article-title":"Internal symmetry in protein structures: prevalence, functional relevance and evolution","volume":"32","author":"Santhanam","year":"2015","journal-title":"Curr. Opin. Struct. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0140","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.str.2011.10.021","article-title":"Modular evolution and the origins of symmetry: reconstruction of a three-fold symmetric globular protein","volume":"20","author":"Broom","year":"2012","journal-title":"Structure"},{"key":"10.1016\/j.trechm.2026.03.001_bb0145","doi-asserted-by":"crossref","first-page":"5943","DOI":"10.1038\/s41598-017-06332-7","article-title":"Computational design of a symmetrical \u03b2-trefoil lectin with cancer cell binding activity","volume":"7","author":"Terada","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.trechm.2026.03.001_bb0150","doi-asserted-by":"crossref","first-page":"15102","DOI":"10.1073\/pnas.1412768111","article-title":"Computational design of a self-assembling symmetrical \u03b2-propeller protein","volume":"111","author":"Voet","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0155","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nchembio.1966","article-title":"De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy","volume":"12","author":"Huang","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0160","doi-asserted-by":"crossref","first-page":"14557","DOI":"10.1073\/pnas.1905643116","article-title":"De novo design of symmetric ferredoxins that shuttle electrons in vivo","volume":"116","author":"Mutter","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0165","doi-asserted-by":"crossref","first-page":"15998","DOI":"10.1021\/jacs.1c05367","article-title":"Seven amino acid types suffice to create the core fold of RNA polymerase","volume":"143","author":"Yagi","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.trechm.2026.03.001_bb0170","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.str.2013.09.003","article-title":"Alternative folding nuclei definitions facilitate the evolution of a symmetric protein fold from a smaller peptide motif","volume":"21","author":"Longo","year":"2013","journal-title":"Structure"},{"key":"10.1016\/j.trechm.2026.03.001_bb0175","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2113883119","article-title":"Symmetry and simplicity spontaneously emerge from the algorithmic nature of evolution","volume":"119","author":"Johnston","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0180","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.jmb.2010.03.057","article-title":"Computational and experimental evidence for the evolution of a (beta alpha)8-barrel protein from an ancestral quarter-barrel stabilised by disulfide bonds","volume":"398","author":"Richter","year":"2010","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0185","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/B978-0-12-386931-9.00002-7","article-title":"Structural, evolutionary, and assembly principles of protein oligomerization","volume":"117","author":"Levy","year":"2013","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"10.1016\/j.trechm.2026.03.001_bb0190","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10409238.2021.1957764","article-title":"The evolutionary history of the HUP domain","volume":"57","author":"Gruic-Sovulj","year":"2022","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0195","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0003-9861(79)90338-2","article-title":"Studies on adenosine triphosphate transphosphorylases XIV. Equilibrium binding properties of the crystalline rabbit and calf muscle ATP-AMP transphosphorylase (adenylate kinase) and derived peptide fragments","volume":"195","author":"Hamada","year":"1979","journal-title":"Arch. Biochem. Biophys."},{"key":"10.1016\/j.trechm.2026.03.001_bb0200","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0021-9258(19)35427-4","article-title":"Mitochondrial ATP synthase. Interaction of a synthetic 50-amino acid, beta-subunit peptide with ATP","volume":"263","author":"Garboczi","year":"1988","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.trechm.2026.03.001_bb0205","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1509508112","article-title":"Control over overall shape and size in de novo designed proteins","volume":"112","author":"Lin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0210","doi-asserted-by":"crossref","first-page":"E11943","DOI":"10.1073\/pnas.1812400115","article-title":"Simple yet functional phosphate-loop proteins","volume":"115","author":"Romero Romero","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0215","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2016131118","article-title":"Helicase-like functions in phosphate loop containing beta-alpha polypeptides","volume":"118","author":"Vyas","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0220","doi-asserted-by":"crossref","first-page":"8344","DOI":"10.1021\/jacs.2c08636","article-title":"On the origins of enzymes: phosphate-binding polypeptides mediate phosphoryl transfer to synthesize adenosine triphosphate","volume":"145","author":"Vyas","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.trechm.2026.03.001_bb0225","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.molcel.2007.02.010","article-title":"A minimal TrpRS catalytic domain supports sense\/antisense ancestry of class I and II aminoacyl-tRNA synthetases","volume":"25","author":"Pham","year":"2007","journal-title":"Mol. Cell"},{"key":"10.1016\/j.trechm.2026.03.001_bb0230","doi-asserted-by":"crossref","first-page":"19710","DOI":"10.1074\/jbc.M115.642876","article-title":"Functional class I and II amino acid-activating enzymes can be coded by opposite strands of the same gene","volume":"290","author":"Martinez-Rodriguez","year":"2015","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.trechm.2026.03.001_bb0235","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.3390\/ijms23084229","article-title":"A leucyl-tRNA synthetase urzyme: authenticity of tRNA synthetase catalytic activities and promiscuous phosphorylation of leucyl-5\u2032AMP","volume":"23","author":"Hobson","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.trechm.2026.03.001_bb0240","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1093\/nar\/gkad1160","article-title":"Enzymic recognition of amino acids drove the evolution of primordial genetic codes","volume":"52","author":"Douglas","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.trechm.2026.03.001_bb0245","doi-asserted-by":"crossref","DOI":"10.1016\/j.biosystems.2021.104481","article-title":"Amino acid activation analysis of primitive aminoacyl-tRNA synthetases encoded by both strands of a single gene using the malachite green assay","volume":"208","author":"Onodera","year":"2021","journal-title":"Biosystems"},{"key":"10.1016\/j.trechm.2026.03.001_bb0250","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1021\/acschembio.5b01011","article-title":"An ancestral tryptophanyl-tRNA synthetase precursor achieves high catalytic rate enhancement without ordered ground-state tertiary structures","volume":"11","author":"Sapienza","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0255","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1093\/nar\/gkae417","article-title":"Primordial aminoacyl-tRNA synthetases preferred minihelices to full-length tRNA","volume":"52","author":"Tang","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.trechm.2026.03.001_bb0260","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s44431-025-00005-6","article-title":"Artificial intelligence-driven approaches for the rational design of peptides with predictable aggregation propensity","volume":"1","author":"Yang","year":"2025","journal-title":"NPJ Soft Matter"},{"key":"10.1016\/j.trechm.2026.03.001_bb0265","article-title":"ACPOpt: a deep learning approach to design structure-aware property optimized anti-cancer peptides","author":"Raghavachary","year":"2025","journal-title":"ChemRxiv"},{"key":"10.1016\/j.trechm.2026.03.001_bb0270","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nrm.2017.58","article-title":"Classification and function of small open reading frames","volume":"18","author":"Couso","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0275","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.str.2022.11.012","article-title":"Benchmarking AlphaFold2 on peptide structure prediction","volume":"31","author":"McDonald","year":"2023","journal-title":"Structure"},{"key":"10.1016\/j.trechm.2026.03.001_bb0280","doi-asserted-by":"crossref","first-page":"4745","DOI":"10.1021\/ct500592m","article-title":"Improved PEP-FOLD approach for peptide and miniprotein structure prediction","volume":"10","author":"Shen","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"10.1016\/j.trechm.2026.03.001_bb0285","article-title":"An integrative multitiered computational analysis for better understanding the structure and function of 85 miniproteins","volume":"7","author":"Veluri","year":"2025","journal-title":"NAR Genom. Bioinform."},{"key":"10.1016\/j.trechm.2026.03.001_bb0290","doi-asserted-by":"crossref","first-page":"15041","DOI":"10.1073\/pnas.93.26.15041","article-title":"Ferredoxin and ferredoxin-heme maquettes","volume":"93","author":"Gibney","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0295","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1002\/prot.24038","article-title":"A synthetic hexapeptide designed to resemble a proteinaceous P-loop nest is shown to bind inorganic phosphate","volume":"80","author":"Bianchi","year":"2012","journal-title":"Proteins"},{"key":"10.1016\/j.trechm.2026.03.001_bb0300","doi-asserted-by":"crossref","DOI":"10.1093\/molbev\/msaf055","article-title":"Redefining the limits of functional continuity in the early evolution of P-loop NTPases","volume":"42","author":"Demkiv","year":"2025","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0305","article-title":"Peptides at vesicle and mineral prebiotic interfaces","author":"Cherepashuk","year":"2025","journal-title":"bioRxiv"},{"key":"10.1016\/j.trechm.2026.03.001_bb0310","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/molbev\/msab017","article-title":"Bridging themes: short protein segments found in different architectures","volume":"38","author":"Kolodny","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0315","doi-asserted-by":"crossref","first-page":"11691","DOI":"10.1073\/pnas.1403395111","article-title":"Global view of the protein universe","volume":"111","author":"Nepomnyachiy","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0320","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/nchembio.1579","article-title":"Evolutionary relationship of two ancient protein superfolds","volume":"10","author":"Far\u00edas-Rico","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0325","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.64415","article-title":"On the emergence of P-Loop NTPase and Rossmann enzymes from a beta-alpha-beta ancestral fragment","volume":"9","author":"Longo","year":"2020","journal-title":"eLife"},{"key":"10.1016\/j.trechm.2026.03.001_bb0330","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00239-015-9722-8","article-title":"The TIM barrel architecture facilitated the early evolution of protein-mediated metabolism","volume":"82","author":"Goldman","year":"2016","journal-title":"J. Mol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0335","doi-asserted-by":"crossref","DOI":"10.1016\/j.jmb.2020.166788","article-title":"A fifth of the protein world: Rossmann-like proteins as an evolutionarily successful structural unit","volume":"433","author":"Medvedev","year":"2021","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0340","doi-asserted-by":"crossref","first-page":"5310","DOI":"10.1073\/pnas.1911742117","article-title":"Short and simple sequences favored the emergence of N-helix phospho-ligand binding sites in the first enzymes","volume":"117","author":"Longo","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0345","doi-asserted-by":"crossref","first-page":"7193","DOI":"10.1073\/pnas.1914982117","article-title":"Small protein folds at the root of an ancient metabolic network","volume":"117","author":"Raanan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0350","article-title":"The history of enzyme evolution embedded in metabolism","author":"Corlett","year":"2025","journal-title":"bioRxiv"},{"key":"10.1016\/j.trechm.2026.03.001_bb0355","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature11600","article-title":"Principles for designing ideal protein structures","volume":"491","author":"Koga","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.trechm.2026.03.001_bb0360","doi-asserted-by":"crossref","first-page":"13549","DOI":"10.1073\/pnas.222243999","article-title":"Combinatorial mutagenesis to restrict amino acid usage in an enzyme to a reduced set","volume":"99","author":"Akanuma","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0365","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1093\/molbev\/msx086","article-title":"Frozen in time: the history of proteins","volume":"34","author":"Kovacs","year":"2017","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0370","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2207897119","article-title":"Creative destruction: new protein folds from old","volume":"119","author":"Alvarez-Carre\u00f1o","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0375","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.sbi.2008.02.006","article-title":"Cradle-loop barrels and the concept of metafolds in protein classification by natural descent","volume":"18","author":"Alva","year":"2008","journal-title":"Curr. Opin. Struct. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0380","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abj3984","article-title":"Quantifying structural relationships of metal-binding sites suggests origins of biological electron transfer","volume":"8","author":"Bromberg","year":"2022","journal-title":"Sci. Adv."},{"key":"10.1016\/j.trechm.2026.03.001_bb0385","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0301-4622(02)00290-9","article-title":"Multiple methionine substitutions are tolerated in T4 lysozyme and have coupled effects on folding and stability","volume":"100","author":"Gassner","year":"2003","journal-title":"Biophys. Chem."},{"key":"10.1016\/j.trechm.2026.03.001_bb0390","doi-asserted-by":"crossref","first-page":"8373","DOI":"10.1073\/pnas.91.18.8373","article-title":"Design of a \u201cminimal\u201d homeodomain: the N-terminal arm modulates DNA binding affinity and stabilizes homeodomain structure","volume":"91","author":"Shang","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0395","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/nsb1097-805","article-title":"Functional rapidly folding proteins from simplified amino acid sequences","volume":"4","author":"Riddle","year":"1997","journal-title":"Nat. Struct. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0400","doi-asserted-by":"crossref","first-page":"37742","DOI":"10.1074\/jbc.M507210200","article-title":"An active enzyme constructed from a 9-amino acid alphabet","volume":"280","author":"Walter","year":"2005","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.trechm.2026.03.001_bb0405","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/s41598-018-19561-1","article-title":"Comprehensive reduction of amino acid set in a protein suggests the importance of prebiotic amino acids for stable proteins","volume":"8","author":"Shibue","year":"2018","journal-title":"Sci. Rep."},{"key":"10.1016\/j.trechm.2026.03.001_bb0410","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s00239-022-10078-w","article-title":"Ancestral sequence reconstruction of the ribosomal protein uS8 and reduction of amino acid usage to a smaller alphabet","volume":"91","author":"Zhao","year":"2023","journal-title":"J. Mol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0415","doi-asserted-by":"crossref","first-page":"5705","DOI":"10.1073\/pnas.1118640109","article-title":"Folding without charges","volume":"109","author":"Kurnik","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0420","doi-asserted-by":"crossref","first-page":"16623","DOI":"10.1073\/pnas.0606843103","article-title":"A backbone-based theory of protein folding","volume":"103","author":"Rose","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0425","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1073\/pnas.0605504103","article-title":"The role of hydrophobic interactions in initiation and propagation of protein folding","volume":"103","author":"Dyson","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.trechm.2026.03.001_bb0430","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1006\/jmbi.1996.0677","article-title":"Hyperthermophile protein folding thermodynamics: differential scanning calorimetry and chemical denaturation of Sac7d","volume":"264","author":"McCrary","year":"1996","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0435","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/prot.10016","article-title":"Why are proteins marginally stable?","volume":"46","author":"Taverna","year":"2002","journal-title":"Proteins"},{"key":"10.1016\/j.trechm.2026.03.001_bb0440","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1110\/ps.4210102","article-title":"Natively unfolded proteins: a point where biology waits for physics","volume":"11","author":"Uversky","year":"2002","journal-title":"Protein Sci."},{"key":"10.1016\/j.trechm.2026.03.001_bb0445","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/s41580-023-00673-0","article-title":"The molecular basis for cellular function of intrinsically disordered protein regions","volume":"25","author":"Holehouse","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0450","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00239-020-09948-y","article-title":"Evolutionary processes and biophysical mechanisms: revisiting why evolved proteins are marginally stable","volume":"88","author":"Wilson","year":"2020","journal-title":"J. Mol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0455","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1126\/science.1169375","article-title":"Protein dynamism and evolvability","volume":"324","author":"Tokuriki","year":"2009","journal-title":"Science"},{"key":"10.1016\/j.trechm.2026.03.001_bb0460","doi-asserted-by":"crossref","first-page":"7359","DOI":"10.1039\/D3CS00594A","article-title":"The protometabolic nature of prebiotic chemistry","volume":"52","author":"Nogal","year":"2023","journal-title":"Chem. Soc. Rev."},{"key":"10.1016\/j.trechm.2026.03.001_bb0465","doi-asserted-by":"crossref","first-page":"11275","DOI":"10.1093\/nar\/gku837","article-title":"Endogenous polyamine function\u2014the RNA perspective","volume":"42","author":"Lightfoot","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.trechm.2026.03.001_bb0470","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1016\/j.jmb.2015.06.020","article-title":"Remaining mysteries of molecular biology: the role of polyamines in the cell","volume":"427","author":"Miller-Fleming","year":"2015","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0475","doi-asserted-by":"crossref","first-page":"5487","DOI":"10.1038\/s41467-021-25530-6","article-title":"Proliferating coacervate droplets as the missing link between chemistry and biology in the origins of life","volume":"12","author":"Matsuo","year":"2021","journal-title":"Nat. Commun."},{"key":"10.1016\/j.trechm.2026.03.001_bb0480","doi-asserted-by":"crossref","first-page":"9368","DOI":"10.1038\/s41467-024-53699-z","article-title":"Catalytic peptide-based coacervates for enhanced function through structural organization and substrate specificity","volume":"15","author":"Reis","year":"2024","journal-title":"Nat. Commun."},{"key":"10.1016\/j.trechm.2026.03.001_bb0485","doi-asserted-by":"crossref","first-page":"8765","DOI":"10.1038\/s41467-025-63656-z","article-title":"RNA-peptide interactions tune the ribozyme activity within coacervate microdroplet dispersions","volume":"16","author":"Ghosh","year":"2025","journal-title":"Nat. Commun."},{"key":"10.1016\/j.trechm.2026.03.001_bb0490","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1009833","article-title":"Evidence for the emergence of \u03b2-trefoils by \u2018Peptide Budding\u2019 from an IgG-like \u03b2-sandwich","volume":"18","author":"Longo","year":"2022","journal-title":"PLoS Comput. Biol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0495","doi-asserted-by":"crossref","first-page":"5134","DOI":"10.1093\/molbev\/msab240","article-title":"Fold evolution before LUCA: common ancestry of SH3 domains and OB domains","volume":"38","author":"Alvarez-Carre\u00f1o","year":"2021","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.trechm.2026.03.001_bb0500","article-title":"Contrastive learning unites sequence and structure in a global representation of protein space","author":"Yanai","year":"2025","journal-title":"bioRxiv"}],"container-title":["Trends in Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S258959742600047X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S258959742600047X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:13:05Z","timestamp":1789600385000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S258959742600047X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":100,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["S258959742600047X"],"URL":"https:\/\/doi.org\/10.1016\/j.trechm.2026.03.001","relation":{},"ISSN":["2589-5974"],"issn-type":[{"value":"2589-5974","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"The borderlands of foldability: lessons from simplified proteins","name":"articletitle","label":"Article Title"},{"value":"Trends in Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.trechm.2026.03.001","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}