Nonequilibrium molecular dynamics simulations of infrared laser-induced dissociation of a tetrameric Aβ42 β-barrel in a neuronal membrane model
Introduction
The aggregation of the amyloid-β (Aβ) proteins, composed primarily of 40 and 42 amino acids, into transient oligomers and ordered amyloid fibrils is one hallmark of Alzheimer's disease (AD) (Dobson, 2002). Although the molecular mechanisms of the toxicity are still debated, a growing body of studies has suggested that the interaction between Aβ proteins and cell membranes is a source of AD pathogenicity (Eisenberg and Jucker, 2012, Butterfield and Lashuel, 2010, Kayed et al., 2004, Lashuel et al., 2002, Jang et al., 2013, Zhang et al., 2017, Kotler et al., 2014, Chang et al., 2011). It has been proposed that the electrostatic interactions drive the binding of Aβ proteins to the membrane and the initial insertion. Then, mainly hydrophobic interactions drive the formation of pores with different topologies (Jang et al., 2014, Strodel et al., 2010, Chandra et al., 2018, Hernandez et al., 2018, Sciacca et al., 2012, Serra-Batiste et al., 2016), though this process is modulated by lipid composition. For instance, Carulla and colleagues showed that the Aβ42, but not Aβ40, assembles into β-barrels (Serra-Batiste et al., 2016), and they recently proposed a NMR-derived model for a tetrameric Aβ42 β-barrel in membrane models (Ciudad et al., 2020). Based on low-resolution experimental data and extensive atomistic replica exchange molecular dynamics (MD) simulations, we have proposed the 3D structure of a Aβ42-barrel consisting of four subunits with an inner pore diameter of ∼ 0.7 nm. The simulation showed that this β-barrel exists with a small probability in bulk solution or in a membrane environment. In contrast, the same tetrameric barrel made of Aβ40 peptides does not exist in bulk solution or in a membrane environment (Nguyen et al., 2019b, 2019c), in full agreement with all experimental data. Interestingly, the A2T and D23N mutations do not change the probability of this Aβ42 β-barrel in a lipid bilayer as reported by replica exchange MD simulations (Ngo et al., 2020).
The formation of Aβ pores could create an unbalance between the inside and outside of the cell, enabling Ca2+ influx through pores (Arispe et al., 1993, Kawahara et al., 2000, Sciacca et al., 2013). The increase of Ca2+ level inside cells causes several biological effects, including cell apoptosis (Mattson and Chan, 2003), endoplasmic reticulum stress response (Alberdi et al., 2013) and acceleration of the generation of reactive oxygen species (Huang et al., 1999), which contribute to the pathology of AD (Tabner et al., 2001). Therefore, small drugs that block the formation of the Ca2+ channel should represent a potential therapeutic approach for AD (Anekonda and Quinn, 2011, Anekonda et al., 2011, Diaz et al., 2009, Zhang et al., 2016, Kato-Negishi and Kawahara, 2008, Arispe et al., 2010). However, despite intensive studies, we still lack effective drugs targeting amyloid-beta that can restore cognitive impairment of AD (Doig et al., 2017).
This repetitive failure has motivated the search for alternative methods. For example, ultrasound has been demonstrated to be a promising method to destabilise amyloid fibrils in in-silico (Okumura and Itoh, 2014, Man et al., 2016b), in-vitro (Chatani et al., 2009, Yagi et al., 2013) and in-vivo studies (Leinenga, 2015). Protein modification is another approach in which molecular photoswitches, such as azobenzene chromophore, are included into the amyloid proteins. This guarantees that a light excitation can switch the system from favorable to unfavorable aggregates, resulting in protein disassembly (Waldauer et al., 2012, Johny et al., 2017, Deeg et al., 2011, Deeg et al., 2012, Measey and Gai, 2012, Hoppmann et al., 2012, Doran et al., 2012). Mid-infrared free electron laser (FEL) experiment with specific oscillation characteristics of a picosecond pulse structure and a tunable wavelength has also been developed and applied to dissociate amyloid fibrils of lysozyme, insulin and short peptide fragments of the thyroid and calcitonin hormones in in-vitro (Kawasaki et al., 2012, 2014a, 2014b, 2014c, 2019).
The molecular dissociation mechanisms from amyloid fibril to oligomers have been studied by laser-induced NEMD simulations. We confirmed that the resonance between the laser field and the amide I vibrational band of the fibril causes fibril dissociation (Man et al., 2015a, Kawasaki et al., 2020). The 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 (Kawasaki et al., 2020). Importantly, these NEMD simulations showed that the surrounding water, nonamyloid proteins with well-defined topologies and DNA molecules are hardly affected by laser irradiation, demonstrating the laser frequency selectivity for amyloid fibril dissociation (Man et al., 2015a).
Motivated by the strong hypothesis that Aβ oligomer pores in cell membrane is related to neurotoxicity in AD, and the absence of experimental and theoretical evidences that laser irradiation can destabilize structured pore oligomers in a micelle and a vesicle, we have carried out laser-induced NEMD simulations on a tetrameric Aβ42 β-barrel in a neuronal membrane model. Our NEMD simulations show that the resonance between the laser field and the amide I vibrational mode converts the initial topology to a random-coil rich disordered structure. Starting from this disordered structure, extensive standard MD simulations show sampling of disordered Aβ42 states without any increase of β-sheets and reports that the orientational order of the lipids is minimally affected. Interestingly, the frequency to be employed to dissociate this β-barrel is specific to the amino acid sequence.
Section snippets
The laser-induced simulation method
It is useful to recall some aspects of the laser-induced simulation method here, and the readers are referred to Refs. Man et al. (2015a, 2015b, 2016a, 2016c), Domin et al. (2018), Kawasaki et al. (2020) for more details. In the simulation, a time-dependent electric fieldis applied to mimic a laser micro-pulse. Here, E0 represents the amplitude of the electric field, σ is the pulse width, t is the time after the pulse maximum t0, c is the speed of light
Determination of the resonance frequency for the Aβ42 β-barrel
As we know that the resonance between the laser field and the amide I band of the fibril leads to dissociation (Man et al., 2015a, Kawasaki et al., 2020), we first identified the amide I bands of the Aβ42 β-barrel. Normal mode analysis in gas phase using an all-atom representation of the 100 MD-generated structures results in an averaged IR spectrum shown in (Fig. 2(A)). It displays a dominant peak around 1681 cm−1 which is assigned to the stretching vibration of the C=O bonds pertaining to the
Conclusions
In summary, we have carried out a laser-induced NEMD simulation to determine whether we could destabilise the tetrameric Aβ42 β-barrel in a neuronal membrane model. We show that the barrel is fully dissociated due to the resonance between the laser field with the amide I vibrational mode of the barrel. Overall, the dissociated structures are quite different from the oligomers in solution as observed by experiments and simulations. Our structures posses highly random coil population with very
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
This work has been supported by the Department of Science and Technology at Ho Chi Minh City, Vietnam (grant 13/2020/HD-QPTKHCN), the “Initiative d’Excellence”, a program from the French State (Grant “DYNAMO”, ANR-11-LABX-0011-01, and “CACSICE”, ANR-11-EQPX-0008), and the National Institutes of Health (R01-GM079383, R21-GM097617, P30-DA035778). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or
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- 1
University of Pittsburgh School of Pharmacy.
- 2
Laboratory of Theoretical Chemistry.
- 3
Faculty of Pharmacy.
- 4
CNRS.
- 5
Institut de Biologie Physico-Chimique.