Lipid Bilayer Interactions of Amyloidogenic N-Terminal Fragment of Apolipoprotein A-I Probed by Forster Resonance Energy Transfer and Molecular Dynamics Simulations

The effects of one of the amyloidogenic mutations of apolipoprotein A-I (apoA-I), G26R, on the thermal stability, structural dynamics and lipid-associating properties of the 1-83 N-terminal fragment of apoA-I (A83) have been investigated using the Forster resonance energy transfer (FRET) and molecular dynamics (MD) simulation. The measurements of FRET between the tryptophan residues of the single Trp variants of A83 as donors and the membrane-incorporated fluorescent probe 4-dimethylaminochalcone as an acceptor provided evidence for a less depth of A83/G26R penetration into phosphatidylcholine (PC) bilayer compared to WT counterpart. The unfolding MD simulations showed that G26R mutation destabilizes the overall structure of A83, with individual alpha-helices differing in their thermal stability. The MD simulations performed at physiological temperature revealed that A83 and A83/G26R differ in their conformational behavior in an aqueous solution, PC and PC/Cholesterol bilayers. These findings may prove of importance for deeper understanding of the key determinants of apoA-I amyloidogenesis.