{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:07:00Z","timestamp":1777554420051,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,25]]},"group-title":"Biophysics","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Elucidating the structure and dynamics of insulin and its analogs has been of broad interest, while presenting challenges due to the unique structural dynamics of insulin (composed itself of two multiply cross-linked peptides A and B) and its ability to assemble in a variety of oligomeric structures under physiological conditions. Here, we present two distinct X-ray crystallographic structures of the long-acting human insulin analog detemir (INSD) resolved in hexameric and dodecameric (or dihexameric) states at 2.85 \u00c5 and 2.70 \u00c5 resolution, respectively, using diffraction data collected under ambient temperature conditions. Characterization of the collective dynamics of these oligomers using the Gaussian Network Model (GNM) reveals several key features: (i) Oligomerization imparts high cooperativity in structural dynamics evidenced by dissection of the cross-correlations at various hierarchical levels; (ii) detemir monomers\u2019 conformational flexibility is highly suppressed within oligomeric constructs, the effect being particularly strong in the dihexamer due to the asymmetric packing of the hexamers and the presence of myristoyl groups at B peptides termini whose interactions imparts further heterogeneities; and (iii) a number of key residues retain, however, their intrinsic dynamics, to be deployed upon release from the oligomers. We distinguish in particular residues serving as hinge sites that mediates the conformational dynamics of the asymmetric units (dimers) and monomers (I2\n                  <jats:sub>A<\/jats:sub>\n                  \u2013V3\n                  <jats:sub>A<\/jats:sub>\n                  and Y19\n                  <jats:sub>A<\/jats:sub>\n                  \u2013C20\n                  <jats:sub>A,<\/jats:sub>\n                  and L11\n                  <jats:sub>B<\/jats:sub>\n                  -L15\n                  <jats:sub>B<\/jats:sub>\n                  and Y26\n                  <jats:sub>B<\/jats:sub>\n                  of the respective peptides A and B), or as anchors supporting structural stability (disulfide-bridge forming cysteines, plus selected residues such as L16\n                  <jats:sub>A,<\/jats:sub>\n                  G8\n                  <jats:sub>B<\/jats:sub>\n                  and R22\n                  <jats:sub>B<\/jats:sub>\n                  -F24\n                  <jats:sub>B<\/jats:sub>\n                  . Overall, this study provides a structural\u2013dynamic framework for gaining new insights into the dynamics of long-acting analog INSD and helps identify actionable sites for modulating insulin (analogs) dynamics toward designing more effective therapeutics.\n                <\/jats:p>","DOI":"10.64898\/2026.04.23.720485","type":"posted-content","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T06:10:14Z","timestamp":1777183814000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure and Dynamics of a Long-Acting Insulin Analog in Hexameric and Dihexameric States"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7906-4426","authenticated-orcid":false,"given":"Esra","family":"Ayan","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Science, Ko\u00e7 University, Istanbul 34450, 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