Cross Dimerization of Amyloid-β and αSynuclein Proteins in Aqueous Environment: A Molecular Dynamics Simulations Study
| Autor: | Prathit Chatterjee, Jaya C. Jose, Neelanjana Sengupta |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Computer and Information Sciences
Amyloid beta Science Entropy Biophysics Molecular Dynamics Simulation Bioinformatics Biochemistry chemistry.chemical_compound Molecular dynamics Alzheimer Disease medicine Humans Protein Interaction Maps Molecular Biology Computerized Simulations Alpha-synuclein Principal Component Analysis Multidisciplinary Aqueous solution Amyloid beta-Peptides biology Lewy body Chemistry Biology and Life Sciences Computational Biology Water medicine.disease In vitro biology.protein alpha-Synuclein Medicine Alzheimer's disease Dimerization Hydrophobic and Hydrophilic Interactions Entropy (order and disorder) Research Article Neuroscience Computer Modeling |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 9, p e106883 (2014) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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