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While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human A\u03b2 variants,<jats:italic>i.e<\/jats:italic>. A2T and A2V, in the heterozygous state. The mixture of A2V A\u03b21-6 (A\u03b2<jats:sub>6<\/jats:sub>) hexapeptide and WT A\u03b21\u201342 (\u0391\u03b2<jats:sub>42<\/jats:sub>) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T A\u03b2<jats:sub>6<\/jats:sub>hexapeptide binding on the monomeric WT A\u03b2<jats:sub>42<\/jats:sub>landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of A\u03b2<jats:sub>42<\/jats:sub>with the A2V and A2T hexapeptides compared to WT A\u03b2<jats:sub>6<\/jats:sub>. A notable reorganization of the A\u03b2<jats:sub>42<\/jats:sub>landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, A\u03b2<jats:sub>6<\/jats:sub>-bound A\u03b2<jats:sub>42<\/jats:sub>monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound A\u03b2<jats:sub>42<\/jats:sub>is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the A\u03b2<jats:sub>42<\/jats:sub>monomer structure, which might help in explaining their reported amyloid inhibition properties.<\/jats:p>","DOI":"10.1038\/s41598-017-10212-5","type":"journal-article","created":{"date-parts":[[2017,8,24]],"date-time":"2017-08-24T09:22:47Z","timestamp":1503566567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors"],"prefix":"10.1038","volume":"7","author":[{"given":"Srirupa","family":"Chakraborty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payel","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,30]]},"reference":[{"key":"10212_CR1","unstructured":"Dementia, Fact Sheet No 362, WHO Media Centre, (April 2016), http:\/\/www.who.int\/mediacentre\/factsheets\/fs362\/en\/."},{"key":"10212_CR2","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1126\/science.275.5300.630","volume":"275","author":"DJ Selkoe","year":"1997","unstructured":"Selkoe, D. 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