Cross dimerization of amyloid-beta and alpha synuclein proteins in aqueous environment: a molecular dynamics simulations study

TitleCross dimerization of amyloid-beta and alpha synuclein proteins in aqueous environment: a molecular dynamics simulations study
Publication TypeJournal Article
Year of Publication2014
AuthorsJose, JC, Chatterjee, P, Sengupta, N
JournalPlos One
Volume9
Issue9
PaginationArticle No. : e106883
Date PublishedSEP
ISSN1932-6203
Abstract

Self-assembly of the intrinsically unstructured proteins, amyloid beta (A beta) and alpha synclein (alpha Syn), 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 A beta and alpha Syn 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 alpha Syn(1-95) and A beta(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 alpha Syn(1-95) 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 alpha Syn(1-95) came in contact with the hydrophobic core of A beta(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.

DOI10.1371/journal.pone.0106883
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)

3.057

Divison category: 
Physical and Materials Chemistry