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They control the chance of proteins unfolding, which can lead to aggregation and loss of transparency. \u03b2B2\u2010Crystallin orthologs are of low stability and comprise two typical \u03b2\u03b3\u2010crystallin domains, although, uniquely, the N\u2010terminal domain has a cysteine in one of the conserved folded \u03b2\u2010hairpins. Using high\u2010temperature (500 K) molecular dynamics simulations with explicit solvent on the N\u2010terminal domain of rodent \u03b2B2\u2010crystallin, we have identified in silico local flexibility in this folded \u03b2\u2010hairpin. We have shown in vitro using two\u2010domain human \u03b2B2\u2010crystallin that replacement of this cysteine with a more usual aromatic residue (phenylalanine) results in a gain in conformational stability and a reduction in the rate of unfolding. We have used principal components analysis to visualize and cluster the coordinates from eight separate simulated unfolding trajectories of both the wild\u2010type and the C50F mutant N\u2010terminal domains. These data, representing fluctuations around the native well, show that although the mutant and wild\u2010type appear to behave similarly over the early time period, the wild type appears to explore a different region of conformational space. It is proposed that the advantage of having this low\u2010stability cysteine may be correlated with a subunit\u2010exchange mechanism that allows \u03b2B2\u2010crystallin to interact with a range of other \u03b2\u2010crystallin subunits.<\/jats:p>","DOI":"10.1110\/ps.041227805","type":"journal-article","created":{"date-parts":[[2005,4,19]],"date-time":"2005-04-19T19:46:44Z","timestamp":1113940004000},"page":"1282-1292","source":"Crossref","is-referenced-by-count":28,"title":["Unfolding crystallins: The destabilizing role of a \u03b2\u2010hairpin cysteine in \u03b2B2\u2010crystallin by simulation and experiment"],"prefix":"10.1002","volume":"14","author":[{"given":"James T.","family":"Macdonald","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew G.","family":"Purkiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myron A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Evans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia M.","family":"Goodfellow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Slingsby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340170408"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4835(92)90100-7"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/exer.2001.1038"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4835(03)00173-8"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/347776a0"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2003.11.012"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/289771a0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.25.13409"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(99)00048-2"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.4197"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1476-9271(03)00048-3"},{"key":"e_1_2_7_13_1","first-page":"103","article-title":"Evolution of the \u03b1\u2010crystallin\/small heat\u2010shock protein family","volume":"10","author":"de Jong W.W.","year":"1993","journal-title":"Mol. 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