{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["11(6)"],"submitter":["Ranganathan S"],"pubmed_abstract":["Proinsulin folding requires dynamic positioning of the C-peptide to guide A- and B-chain alignment and disulfide pairing. Mutant INS-gene-induced diabetes of youth (MIDY) arises when single-residue substitutions disrupt this process. We mapped the conformational free-energy landscapes of wild-type (WT) proinsulin and seven MIDY variants using metadynamics and molecular dynamics simulations. WT exhibits a deep free-energy minimum at compact conformations. In contrast, MIDY mutants display a continuum of destabilization: E-(A4)K retains near-WT stability, <i>Akita</i> (C-(A7)-Y), V-(B18)-A, and R-(Cpep + 2)C show moderate loss of the native basin, while H-(B5)-D, L-(A16)-P, and Y-(B26)C collapse the closed-open barrier and populate misfolded open states >50% of the time. Structural analyses "],"journal":["ACS omega"],"pagination":["9890-9901"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12917636"],"repository":["biostudies-literature"],"pubmed_title":["Unraveling C‑Peptide's Role in MIDY: A Structural Perspective."],"pmcid":["PMC12917636"],"pubmed_authors":["Kilgore P","Dick K","Bishop D","Zavarzadeh P","Arunagiri A","Ranganathan S"],"additional_accession":[]},"is_claimable":false,"name":"Unraveling C‑Peptide's Role in MIDY: A Structural Perspective.","description":"Proinsulin folding requires dynamic positioning of the C-peptide to guide A- and B-chain alignment and disulfide pairing. Mutant INS-gene-induced diabetes of youth (MIDY) arises when single-residue substitutions disrupt this process. We mapped the conformational free-energy landscapes of wild-type (WT) proinsulin and seven MIDY variants using metadynamics and molecular dynamics simulations. WT exhibits a deep free-energy minimum at compact conformations. In contrast, MIDY mutants display a continuum of destabilization: E-(A4)K retains near-WT stability, <i>Akita</i> (C-(A7)-Y), V-(B18)-A, and R-(Cpep + 2)C show moderate loss of the native basin, while H-(B5)-D, L-(A16)-P, and Y-(B26)C collapse the closed-open barrier and populate misfolded open states >50% of the time. Structural analyses ","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-07-16T18:01:05.225Z","creation":"2026-07-09T11:10:40.775Z"},"accession":"S-EPMC12917636","cross_references":{"pubmed":["41726593"],"doi":["10.1021/acsomega.5c10573"]}}