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Rotations of aromatic side chains\u2014so called \u201cring flips\u201d\u2014require transient expansion of the surrounding protein core and represent hallmark examples of transient conformational fluctuations. We recently demonstrated that activation volume and isothermal compressibility provide unique insights into ring flip transition states. Here, we report transition\u2010state compressibilities for four aromatic side chains in bovine pancreatic trypsin inhibitor (BPTI). The compressibilities vary widely, ranging from values typical of unfolded proteins to those of the fully folded state. Notably, transition\u2010state compressibility correlates negatively with activation energy, indicating that the likelihood of a ring flip scales with the degree of expansion in the transition state. Our results show that different structural regions, even within a small protein such as BPTI, display distinct dynamic transitions and volume fluctuations, reflecting varying extents of structural rearrangement along the transition pathways. Thus, isothermal compressibility emerges as a powerful parameter yielding insights into the relationships between ground\u2010state structure and the transition\u2010state expansion during conformational transitions.<\/jats:p>","DOI":"10.1002\/cbic.70442","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:34:41Z","timestamp":1782819281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pressure\u2010Dependent Aromatic Ring Flips Reveal Variable Transition\u2010State Volume and Compressibility Among Structural Regions of BPTI"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7558-3536","authenticated-orcid":false,"given":"Matthias","family":"Dreydoppel","sequence":"first","affiliation":[{"name":"Institute of Physics, Biophysics Martin\u2010Luther\u2010University Halle\u2010Wittenberg  Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2395-825X","authenticated-orcid":false,"given":"Mikael","family":"Akke","sequence":"additional","affiliation":[{"name":"Division of Biophysical Chemistry Center for Molecular Protein Science Department of Chemistry Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0841-8332","authenticated-orcid":false,"given":"Ulrich","family":"Weininger","sequence":"additional","affiliation":[{"name":"Institute of Physics, Biophysics Martin\u2010Luther\u2010University Halle\u2010Wittenberg  Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130258"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066176"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.07.004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1101-923"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.2c07258"},{"key":"e_1_2_9_7_1","first-page":"503","article-title":"Proton Magnetic Resonance Studies of the Tyrosine Residues of Hen Lysozyme\u2014Assignment and Detection of Conformational Mobility","volume":"189","author":"Campbell I. 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