Computational Investigation of the Binding Dynamics of Oligo p-Phenylene Ethynylene Fluorescence Sensors and Aβ Oligomers

Abstract

Amyloid protein aggregates are pathological hallmarks of neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases and are believed to be formed well before the onset of neurodegeneration and cognitive impairment. Monitoring the course of protein aggregation is thus vital to understanding and combating these diseases. We have recently demonstrated that a novel class of fluorescence sensors, oligomeric pphenylene ethynylene (PE)-based electrolytes (OPEs) selectively bind to and detect prefibrillar and fibrillar aggregates of AD-related amyloid-β (Aβ) peptides over monomeric Aβ. In this study, we investigated the binding between two OPEs, anionic OPE 1 2− and cationic OPE 2 4+ , and to two different β-sheet rich Aβ oligomers using classical all-atom molecular dynamics simulations. Our simulations have revealed a number of OPE binding sites on Aβ oligomer surfaces, and these sites feature hydrophobic amino acids as well as oppositely charged amino acids. Binding energy calculations show energetically favorable interactions between both anionic and cationic OPEs with Aβ oligomers. Moreover, OPEs bind as complexes as well as single molecules. Compared to free OPEs, Aβ protofibril bound OPEs show backbone planarization with restricted rotations and reduced hydration of the ethyl ester end groups. These characteristics, along with OPE complexation, align with known mechanisms of binding induced OPE fluorescence turn-on and spectral shifts from a quenched, unbound state in aqueous solutions. This study thus sheds light on the molecular-level details of OPE-Aβ protofibril interactions and provides a structural basis for fluorescence turn-on sensing modes of OPEs.

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

“…After 100 ns of simulation, 11 out of 12 OPE became bound to the protofibril at six different binding sites either as single OPE molecules (sites 1, 4, and 5) or as OPE complexes (sites 2, 3, and 6) (Figure A). This binding pattern is consistent with what we have previously reported in a MD simulation study, where hydrophobic and electrostatic interactions were the main driving forces for binding. Three of the binding sites were located on the β-sheet rich protofibril surface (sites 2, 3, and 6; Figure B,C); one was located on the β-turn (site 5; Figure D), and the last two were at the ends of the protofibril (sites 1 and 4; Figure B,E).…”

A Portrait of the OPE as a Biological Agent

“…Very recently, Evans et al [ 41 ] carried out a computational investigation about the binding dynamics of compounds 19c and 18e ( Table 1 ) toward some Aβ oligomer models using classical all-atom molecular dynamics, in order to understand their interaction with amyloids. The studies were conducted with two β-sheet rich Aβ oligopeptides of 5- and 24-mer.…”

Selective In Vitro and Ex Vivo Staining of Brain Neurofibrillary Tangles and Amyloid Plaques by Novel Ethylene Ethynylene-Based Optical Sensors

“…All these features have been found to be important in OPE's water solubility, photophysical properties, and affinity and selectivity for aggregated protein conformations [14][15][16]21]. Results from simulation studies showed that OPEs bind to protein assemblies such as viral capsids [43] and Aβ40 protofibrils [44] at multiple sites. Binding free energy is dominated by strong van der Waals interactions between the hydrophobic OPE backbone and hydrophobic grooves and patches on the protein surface and favorable electrostatic interactions between the charged moieties on the OPEs and oppositely charged residues around the binding sites on the protein assemblies.…”

“…Binding free energy is dominated by strong van der Waals interactions between the hydrophobic OPE backbone and hydrophobic grooves and patches on the protein surface and favorable electrostatic interactions between the charged moieties on the OPEs and oppositely charged residues around the binding sites on the protein assemblies. Both anionic and cationic OPEs exhibit favorable interactions with Aβ oligomers [44]. Therefore, OPEs are viable as broad protein aggregate sensors and have diagnostic potential against AD and related proteinopathies.…”