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Substituting 4R-Hyp with its diastereomer 4S-Hyp markedly reduces triple-helix thermal stability and impairs collagen function. The origins of this destabilization have mostly been ascribed to stereoelectronic effects such as the gauche effect and n\u00a0\u2192\u00a0\n                    <jats:italic>\u03c0<\/jats:italic>\n                    * interactions. Here, we dissect the role of different stabilizing interactions on molecular conformation using linear infrared and two-dimensional infrared spectroscopy, aided by density functional theory calculations. We investigate the structure of\n                    <jats:italic>N<\/jats:italic>\n                    -Boc-(2S,4S)-4-hydroxyproline-methyl ester (Boc-4S-Hyp-OMe) and\n                    <jats:italic>N<\/jats:italic>\n                    -Boc-(2S,4R)-4-hydroxyproline-methyl ester (Boc-4R-Hyp-OMe) in chloroform solution, a simplified model for the water-deficient environment in collagen tissues where triple helices assemble into fibrils. We find that, while stereoelectronic effects indeed influence molecular conformation, n\u00a0\u2192\u00a0\n                    <jats:italic>\u03c0<\/jats:italic>\n                    * interactions only moderately alter conformational equilibria. Conversely, our results show that hydrogen bonding is pivotal: the conformation of Boc-4S-Hyp-OMe is stabilized by an intramolecular hydrogen bond, whereas Boc-4R-Hyp-OMe primarily forms intermolecular hydrogen bonds, leading to a greater intermolecular affinity. These findings highlight hydrogen bonding as a key determinant of hydroxyproline conformation at the single-residue level.\n                  <\/jats:p>","DOI":"10.1038\/s42004-026-01984-x","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T10:33:53Z","timestamp":1774348433000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stereoelectronic and hydrogen-bonding effects on hydroxyproline conformation"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6071-7030","authenticated-orcid":false,"given":"Fumiki","family":"Matsumura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5964-727X","authenticated-orcid":false,"given":"Pablo","family":"G\u00f3mez Argudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6851-8453","authenticated-orcid":false,"given":"Mischa","family":"Bonn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3417-4987","authenticated-orcid":false,"given":"Giulia","family":"Giubertoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-5220","authenticated-orcid":false,"given":"Johannes","family":"Hunger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"1984_CR1","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","volume":"78","author":"MD Shoulders","year":"2009","unstructured":"Shoulders, M. 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