Cross Dimerization of Amyloid-β and αSynuclein Proteins in Aqueous Environment: A Molecular Dynamics Simulations Study

Abstract

Self-assembly of the intrinsically unstructured proteins, amyloid beta (Aβ) and alpha synclein (αSyn), are associated with Alzheimer’s Disease, and Parkinson’s and Lewy Body Diseases, respectively. Importantly, pathological overlaps between these neurodegenerative diseases, and the possibilities of interactions between Aβ and αSyn in biological milieu emerge from several recent clinical reports and in vitro studies. Nevertheless, there are very few molecular level studies that have probed the nature of spontaneous interactions between these two sequentially dissimilar proteins and key characteristics of the resulting cross complexes. In this study, we have used atomistic molecular dynamics simulations to probe the possibility of cross dimerization between αSyn1–95 and Aβ 1–42, and thereby gain insights into their plausible early assembly pathways in aqueous environment. Our analyses indicate a strong probability of association between the two sequences, with inter-protein attractive electrostatic interactions playing dominant roles. Principal component analysis revealed significant heterogeneity in the strength and nature of the associations in the key interaction modes. In most, the interactions of repeating Lys residues, mainly in the imperfect repeats ‘KTKEGV’ present in αSyn1–95 were found to be essential for cross interactions and formation of inter-protein salt bridges. Additionally, a hydrophobicity driven interaction mode devoid of salt bridges, where the non-amyloid component (NAC) region of αSyn1–95 came in contact with the hydrophobic core of Aβ 1–42 was observed. The existence of such hetero complexes, and therefore hetero assembly pathways may lead to polymorphic aggregates with variations in pathological attributes. Our results provide a perspective on development of therapeutic strategies for preventing pathogenic interactions between these proteins.

Self-assembly of the full-length amyloid Aβ42 protein in dimers

“…43–45 According to ref., 33 sampling during several hundred nanoseconds of aMD simulation is equivalent to sampling in the millisecond time scale for conventional MD (cMD) simulations, suggesting that we should be able to extend the sampling efficiency by several orders of magnitude with aMD. Of note, the aMD approach was recently used to analyze the larger Aβ-αSyn co-assembly system, 46 thereby justifying the suitability of this approach for Aβ42 dimer simulation.…”

Perturbations in inter-domain associations may trigger the onset of pathogenic transformations in PrPC: insights from atomistic simulations

“…Previous studies have asserted that these salt-bridges contribute to the stabilization of PrP C and that their abolition, either due to protonation of the acidic amino acids in response to low pH or by relevant genetic mutations, decreases the stability of PrP C and favors misfolding. [78][79][80][81] Thus, the overall destabilization of the salt bridge network in Y149F may be commensurate with a higher local desolvation barrier resulting from the increased hydration accompanying the dynamical instability in this system. 7a-c, we depict distributions of the salt bridge distances (d SB ) between each pair in the WT and the perturbed Y149F system.…”

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

“…The systems showed a lack of convergence ( Figure 12). It has been recently shown that the cross-dimerisation of IDPs reduces the RMSF of the peptide [41]. The calculations in quasi harmonic approximations are based on the motions of the macromolecules and not take into account the self-entropy due to rotation, translational and conformational changes of the molecule [42].…”