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Molecular dynamics (MD) simulations offer a valuable approach to explore protein folding mechanisms. In the present study, steered molecular dynamics (SMD) simulations were conducted to stretch the polypeptide models along the \u03b1\u2010helix axis in different solvents. The potential of mean force (PMF) associated with nonequilibrium stretching of the polypeptide chain was higher in HFIP than in water and varied depending on amino acid composition and degree of polymerization. HFIP molecules preferentially concentrated in grooves of \u03b1\u2010helical polypeptides. Stretching the polypeptides in HFIP resulted in the formation of 3<jats:sub>10<\/jats:sub>\u2010helix structures, suggesting that local solvation enhances structural stability. Additional SMD simulations of Trp\u2010cage, a mini\u2010protein driven by hydrophobic collapse in protein folding, showed partial unfolding of the \u03b1\u2010helix region and global extension of both termini. The resulting PMF profiles indicate that \u03b1\u2010helices are formed in the early stages of Trp\u2010cage folding. This study offers an analytical framework that can be extended to more complex amino acid sequences and proteins with diverse structural motifs. HFIP appears to play a central role in the \u03b1\u2010helical transformation of higher\u2010order protein structures.<\/jats:p>","DOI":"10.1002\/chem.202502163","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T11:03:23Z","timestamp":1755601403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Solvent\u2010Induced Stabilization and Folding Pathways of \u03b1\u2010Helical Peptides: A Computational Investigation Using Steered Molecular Dynamics"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8016-1338","authenticated-orcid":false,"given":"Takuya","family":"Uto","sequence":"first","affiliation":[{"name":"Faculty of Engineering University of Miyazaki Nishi 1\u20101 Gakuen\u2010Kibanadai Miyazaki 889\u20102192 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hinano","family":"Suenaga","sequence":"additional","affiliation":[{"name":"Faculty of Engineering University of Miyazaki Nishi 1\u20101 Gakuen\u2010Kibanadai Miyazaki 889\u20102192 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-0876","authenticated-orcid":false,"given":"Yu","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Digital Strategy Center Daicel Corporation  3\u20101 Ofuka\u2010cho, Kita\u2010ku Osaka 530\u20100011 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr3000994"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-014-9462-7"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.04.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01249-0"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1994.0015"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1997.1468"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja990833t"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-017-0088"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0279141"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzm082"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp404714c"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi501021r"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911563116"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.06.038"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.0c06476"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.1651473"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.1590311"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct300709u"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.polymer.2008.06.047"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b01024"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00124a002"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00074a030"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/j100142a004"},{"volume-title":"Gaussian 16","year":"2016","author":"Frisch M. 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