Nonequilibrium molecular dynamics simulations of infrared laser-induced dissociation of a tetrameric Aβ42 β-barrel in a neuronal membrane model

Abstract

Experimental studies have reported that the amyloid-β proteins can form pores in cell membranes, and this could be one possible source of toxicity in Alzheimer's disease. Dissociation of these pores could therefore be a potential therapeutic approach. It is known that high photon density free-electron laser experiments and laser-induced nonequilibrium molecular dynamics simulations (NEMD) can dissociate amyloid fibrils at specific frequencies in vitro. Our question is whether NEMD simulations can dissociate amyloid pores in a bilayer mimicking a neuronal membrane, and as an example, we select a tetrameric Aβ42 β-barrel. Our simulations shows that the resonance between the laser field and the amide I vibrational mode of the barrel destabilises all intramolecular and intermolecular hydrogen bonds of Aβ42 and converts the β-barrel to a random/coil disordered oligomer. Starting from this disordered oligomer, extensive standard MD simulations shows sampling of disordered Aβ42 states without any increase of β-sheet and reports that the orientational order of lipids is minimally disturbed. Interestingly, the frequency to be employed to dissociate this beta-barrel is specific to the amino acid sequence. Taken together with our previous simulation results, this study indicates that infrared laser irradiation can dissociate amyloid fibrils and oligomers in bulk solution and in a membrane environment without affecting the surrounding molecules, offering therefore a promising way to retard the progression of AD.