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Previous studies have shown that membrane lipid composition, cholesterol concentration, and mutation in the transmembrane helix modified the structures and fluctuations of C99. In this study, we performed atomistic molecular dynamics simulations of the homodimer of the 55-residue congener of the C-terminal domain of the amyloid protein precursor, C99(1\u201355), in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine-cholesterol lipid bilayer and compared the conformational ensemble of wild-type (WT) sequence to those of the A2T and D23N variants. These mutations are particularly interesting as the protective Alzheimer\u2019s disease (AD) A2T mutation is known to decrease A\u03b2 production, whereas the early onset AD D23N mutation does not affect A\u03b2 production. We found noticeable differences in the structural ensembles of the three sequences. In particular, A2T varies from both WT and D23N by having long-range effects on the population of the extracellular juxtamembrane helix, the interface between the G29xxx-G33xxx-G37 motifs, and the fluctuations of the transmembrane helical topologies.<\/jats:p>","DOI":"10.1063\/5.0101622","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T13:28:23Z","timestamp":1659446903000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Impact of A2T and D23N mutations on C99 homodimer conformations"],"prefix":"10.1063","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9086-3576","authenticated-orcid":false,"given":"Yan","family":"Lu","sequence":"first","affiliation":[{"name":"School of Physics, Xidian University 1 , Xi\u2019an 710071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-829X","authenticated-orcid":false,"suffix":"Jr.","given":"Freddie R.","family":"Salsbury","sequence":"additional","affiliation":[{"name":"Department of Physics, Wake Forest University 2 , Winston-Salem, North Carolina 27106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-5585","authenticated-orcid":false,"given":"Philippe","family":"Derreumaux","sequence":"additional","affiliation":[{"name":"CNRS, Universit\u00e9 Paris Cit\u00e9, UPR 9080, Laboratoire de Biochimie Th\u00e9orique, Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild 3 , 13 Rue Pierre et Marie Curie, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"317","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"2023081006462020700_c1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41582-019-0281-2","article-title":"Cerebral amyloid angiopathy and Alzheimer disease\u2014One peptide, two pathways","volume":"16","year":"2020","journal-title":"Nat. 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