Abstract
ABSTRACT Parkinson’s disease is a progressive neurodegenerative disorder that destroys neurons and the alpha-synuclein (α-syn) fibrils are found at abnormally high concentrations in the brain of the patients. α-Syn fibrils can form distinct polymorphs in seeding activities, contributing differently to synucleinopathies and altering their biological activities. Furthermore, the interaction between the two protofilaments of α-syn fibrils remains unclear at the atomic level despite numerous experimental attempts. Here, we provide insights about interaction mechanism of the interface (residues 50–57) between two protofilaments for wild-type (WT) α-syn and its five familial mutations by using molecular dynamics (MD) simulations with explicit solvation. Our structural analyses for this polymorph show that A53E, A53T and G51D familial mutations are likely to form different protofilaments interfaces, whereas H50Q and A53V are the most probable familial mutations. In addition, we observed that A53V tends to form cross-β structure, thus, it may have a toxic effect in this polymorph. Consequently, the structural insights and findings in this study about disease-related familial mutations may guide the studies of future drug design targeting α-syn fibrils.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.