{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:14:52Z","timestamp":1772118892364,"version":"3.50.1"},"reference-count":64,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The von Willebrand disease (vWD) is the most common hereditary bleeding disorder caused by defects of the von Willebrand Factor (vWF), a large extracellular protein in charge of adhering platelets to sites of vascular lesions. vWF performs this essential homeostatic task via specific protein\u2013protein interactions between the vWF A1 domain and the platelet receptor, the glycoprotein Ib alpha (GPIB\n                    <jats:italic>\u03b1<\/jats:italic>\n                    ). The two naturally occurring vWF A1 domain mutations G1324A and G1324S, near the GPIB\n                    <jats:italic>\u03b1<\/jats:italic>\n                    binding site, induce a dramatic decrease in platelet adhesion, resulting in a bleeding disorder classified as type 2M vWD. However, the reason for the drastic phenotypic response induced by these two supposedly minor modifications remains unclear. We addressed this question using a combination of equilibrium\u2010molecular dynamics (MD) and nonequilibrium MD\u2010based free energy simulations. Our data confirms that both mutations maintain the highly stable Rossmann fold of the vWF A1 domain. G1324A and G1324S mutations hardly changed the per\u2010residue flexibility of the A1 domain but induced a global conformational change affecting the region near the binding site to GPIB\n                    <jats:italic>\u03b1<\/jats:italic>\n                    . Furthermore, we observed two significant changes in the vWF A1 domain upon mutation, the global redistribution of the internal mechanical stress and the increased thermodynamic stability of the A1 domain. These observations are consistent with previously reported mutations increasing the melting temperature. Overall, our results support the idea of thermodynamic conformational restriction of A1\u2014before the binding to GPIB\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \u2014as a crucial factor determining the loss\u2010of\u2010function of the G1324A(S) vWD mutants.\n                  <\/jats:p>","DOI":"10.1002\/prot.26397","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T03:34:41Z","timestamp":1657769681000},"page":"2058-2066","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thermodynamic stabilization of von Willebrand factor\n                    <scp>A1<\/scp>\n                    domain induces protein loss of function"],"prefix":"10.1002","volume":"90","author":[{"given":"Ang\u00e9lica","family":"Sandoval\u2010P\u00e9rez","sequence":"first","affiliation":[{"name":"Max Planck Tandem Group in Computational Biophysics Universidad de Los Andes  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Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Mej\u00eda\u2010Restrepo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilo","family":"Aponte\u2010Santamar\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1601561"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2008.01848.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-378638"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4557-2296-9.00007-5"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-405134"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-01-769018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002654200"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00047.2009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.303016"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04324.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH13-09-0800"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02146.x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3182035931"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.703850"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.02945.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.511220"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2017.05.013"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.09.022"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22634-x"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.504001"},{"issue":"9","key":"e_1_2_10_22_1","first-page":"3195","article-title":"Platelet 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