biostudies-literatureGalpern EANASA | NASA Astrobiology Institute (NAI)Consejo Nacional de Investigaciones Científicas y T#x00E9;cnicasUniversidad de Buenos Aires (UBA)Consejo Nacional de Investigaciones Científicas y T#x00E9;cnicas (CONICET)National Science Foundation (NSF)Universidad de Buenos AiresNASA | NASA Astrobiology InstituteNational Science Foundatione2400151121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11252736biostudies-literatureUnknown121(28)Protein folding and evolution are intimately linked phenomena. Here, we revisit the concept of exons as potential protein folding modules across a set of 38 abundant and conserved protein families. Taking advantage of genomic exon-intron organization and extensive protein sequence data, we explore exon boundary conservation and assess the foldon-like behavior of exons using energy landscape theoretic measurements. We found deviations in the exon size distribution from exponential decay indicating selection in evolution. We show that when taken together there is a pronounced tendency to independent foldability for segments corresponding to the more conserved exons, supporting the idea of exon-foldon correspondence. While 45% of the families follow this general trend when analyzed individualProceedings of the National Academy of Sciences of the United States of AmericaReassessing the exon-foldon correspondence using frustration analysis.PMC11252736UBACyT 20020220200106BAPIP2022-2024 - 11220210100704COPHY-201974580NSSC18M0093Bueno CJaafari HWolynes PGFerreiro DUGalpern EAfalseReassessing the exon-foldon correspondence using frustration analysis.Protein folding and evolution are intimately linked phenomena. Here, we revisit the concept of exons as potential protein folding modules across a set of 38 abundant and conserved protein families. Taking advantage of genomic exon-intron organization and extensive protein sequence data, we explore exon boundary conservation and assess the foldon-like behavior of exons using energy landscape theoretic measurements. We found deviations in the exon size distribution from exponential decay indicating selection in evolution. We show that when taken together there is a pronounced tendency to independent foldability for segments corresponding to the more conserved exons, supporting the idea of exon-foldon correspondence. While 45% of the families follow this general trend when analyzed individual2024-01-01T00:00:00Z2024 Jul2025-04-04T21:49:46.03Z2025-04-04T21:49:46.03ZS-EPMC112527363895454810.1073/pnas.2400151121