{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:25:37Z","timestamp":1790803537928,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2011,5,16]],"date-time":"2011-05-16T00:00:00Z","timestamp":1305504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["GM65372"],"award-info":[{"award-number":["GM65372"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2011,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\u03b2\u2010site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potential target for treating Alzheimer's disease. BACE1's binding site is partially covered by a flexible loop on its N\u2010terminal domain, known as the \u201cflap,\u201d which has been found in several conformations in crystal structures of BACE1 and other aspartyl proteases. The side chain of the invariant residue Tyr71 on the flap adopts several rotameric orientations, leading to our hypothesis that the orientation of this residue dictates the movement and conformations available to the flap. We investigated this hypothesis by performing 220 ns of molecular dynamics simulations of bound and unbound wild\u2010type BACE1 as well as the unbound Y71A mutant. Our findings indicate that the flap exhibits various degrees of mobility and adopts different conformations depending on the Tyr71 orientation. Surprisingly, the \u201cself\u2010inhibited\u201d form is stable in our simulations, making it a reasonable target for drug design. The alanine mutant, lacking a large side chain at position 71, displays significant differences in flap dynamics from wild type, freely sampling very open and closed conformations. Our simulations show that Tyr71, in addition to its previously determined functions in catalysis and substrate binding, has the important role of modulating flap conformations in BACE1. Proteins 2011; \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.23050","type":"journal-article","created":{"date-parts":[[2011,4,5]],"date-time":"2011-04-05T13:55:24Z","timestamp":1302011724000},"page":"2247-2259","source":"Crossref","is-referenced-by-count":25,"title":["The role of tyrosine 71 in modulating the flap conformations of BACE1"],"prefix":"10.1002","volume":"79","author":[{"given":"Steven A.","family":"Spronk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather 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