Characterizing Methyl‐Bearing Side Chain Contacts and Dynamics Mediating Amyloid β Protofibril Interactions Using 13Cmethyl‐DEST and Lifetime Line Broadening1. Issue 39 (11th August 2014)

• Record Type: Journal Article
• Authors: Fawzi, Nicolas L.; Libich, David S.; Ying, Jinfa; Tugarinov, Vitali; Clore, G. Marius
• Is Part Of: Angewandte Chemie international edition. Volume 53:Issue 39(2014)
• Page Start: 10345
• Page End: 10349
• Publication Date: 2014-08-11
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201405180
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced ¹⁵N dark‐state exchange saturation transfer (DEST) and ¹⁵N lifetime line‐broadening to study solution backbone dynamics and position‐specific binding probabilities for amyloid β (Aβ) monomers in exchange with large (2–80 MDa) protofibrillar Aβ aggregates. Here we use ¹³C_methyl DEST and lifetime line‐broadening to probe the interactions and dynamics of methyl‐bearing side chains in the Aβ‐protofibril‐bound state. We show that all methyl groups of Aβ40 populate direct‐contact bound states with a very fast effective transverse relaxation rate, indicative of side‐chain‐mediated direct binding to the protofibril surface. The data are consistent with position‐specific enhancements of ¹³C_methyl‐<inline-formula><alternatives><tex-math notation="tex"><![CDATA[${R{{{\rm tethered}\hfill \atop 2\hfill}}}$]]></tex-math><inline-graphic xlink:href="ark:/27927/pgh1c9n307c" mimetype="image" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></alternatives></inline-formula> values in tethered states, providing further insights into the structural ensemble of the protofibril‐bound state.</p> </abstract>