Premium
Characterizing Methyl‐Bearing Side Chain Contacts and Dynamics Mediating Amyloid β Protofibril Interactions Using 13 C methyl ‐DEST and Lifetime Line Broadening
Author(s) -
Fawzi Nicolas L.,
Libich David S.,
Ying Jinfa,
Tugarinov Vitali,
Clore G. Marius
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201405180
Subject(s) - side chain , chemistry , molecular dynamics , relaxation (psychology) , monomer , saturation (graph theory) , line (geometry) , crystallography , methyl group , computational chemistry , polymer , psychology , social psychology , mathematics , geometry , organic chemistry , combinatorics , alkyl
Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced 15 N dark‐state exchange saturation transfer (DEST) and 15 N 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 13 C 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 13 C methyl ‐ ${R{{{\rm tethered}\hfill \atop 2\hfill}}}$ values in tethered states, providing further insights into the structural ensemble of the protofibril‐bound state.