Infrared Laser-Induced Amyloid Fibril Dissociation: A Joint Experimental/Theoretical Study on the GNNQQNY Peptide

Abstract

Neurodegenerative diseases are usually characterized by plaques made of well-ordered aggregates of distinct amyloid proteins. Dissociating these very stable amyloid plaques is a critical clinical issue. In this study, we present a joint mid-infrared free electron laser experiment/non-equilibrium molecular dynamics simulation to understand the dissociation process of a representative example GNNQQNY fibril. By tuning the laser frequency to the amide I band of the fibril, the resonance takes place and dissociation is occurred. The calculated and observed wide-angle X-ray scattering profiles and secondary structures before and after laser irradiation being identical, we can propose a dissociation mechanism with high confidence from our simulations. We find that dissociation starts in the core of the fibrils by fragmenting the intermolecular hydrogen bonds and separating the peptides and then propagates to the fibril extremities leading to the formation of unstructured expanded oligomers. We suggest that this should be a generic mechanism of the laser-induced dissociation of amyloid fibrils.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…This should be a generic mechanism of the laserinduced dissociation of amyloid fibrils. 1027 We find that the effects of the laser irradiation are determined by a balance between fibril formation and dissociation. Understanding the factors that are responsible for this balance are important.…”

“…At the computational level, we developed a laser-induced nonequilibrium MD simulation method and applied it to study the dissociation process of various fibrils, made of 5-mer U-shape Aβ17–42, 5-mer β-solenoid HET-s, and 200-mer GNNQQNY. , Samples containing amyloid fibrils, DNA duplexes, and globular proteins are also considered, and the simulations show that the surrounding protein and DNA molecules are not affected, demonstrating therefore laser frequency selectivity for dissociation . Simulations showed that the primary step in the dissociation process is due to the strong resonance between the fibril amide I vibrations and the tuned laser frequency and not just the deposited infrared thermal energy.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…This phenomenon is affected by specific lipids including cholesterol, sphingomyelin, and gangliosides [717,718]: lipid types typically present in the outer leaflet of the cell membrane. Amyloid fibers at a membrane surface have thus been frequently studied using MD simulations, e.g., [719][720][721][722][723][724][725][726][727][728][729][730], however, a surprisingly small fraction of this work has been performed in the context of drug design [731,732]. Khondker et al, proposed designing drugs with a mode of action that involved modulating membrane properties to affect the aggregation of amyloid-β25-35 at the bilayer surface [229].…”

Application of mid-infrared free-electron laser for structural analysis of biological materials

“…In the past, MIR-FELs were used for dissociation of protein aggregates such as amyloid fibrils (Kawasaki et al, 2016(Kawasaki et al, , 2018(Kawasaki et al, , 2020a and ablation of tissues in surgical medicine (Hutson et al, 2009;Kanai et al, 2008). However, we have shown another application example of MIR-FELs for exploring the structure of biological materials mediated by the mode-selective irradiation in the current study.…”