![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
Abstract
Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding and aggregation of prion protein (PrP), and the inhibition of PrP aggregation is one of the most effective therapeutic strategies. Proanthocyanidin B2 (PB2) and B3 (PB3), the effective natural antioxidants have been evaluated for the inhibition of amyloid-related protein aggregation. Since PrP has similar aggregation mechanism with other amyloid-related proteins, will PB2 and PB3 affect the aggregation of PrP? In this paper, experimental and molecular dynamics (MD) simulation methods were combined to investigate the influence of PB2 and PB3 on PrP aggregation. Thioflavin T assays showed PB2 and PB3 could inhibit PrP aggregation in a concentrate-dependent manner in vitro. To understand the underlying mechanism, we performed 400 ns all-atom MD simulations. The results suggested PB2 could stabilize the α2 C-terminus and the hydrophobic core of protein by stabilizing two important salt bridges R156-E196 and R156-D202, and consequently made global structure of protein more stable. Surprisingly, PB3 could not stabilize PrP, which may inhibit PrP aggregation through a different mechanism. Since dimerization is the first step of aggregation, will PB3 inhibit PrP aggregation by inhibiting the dimerization? To verify our assumption, we then explored the effect of PB3 on protein dimerization by performing 800 ns MD simulations. The results suggested PB3 could reduce the residue contacts and hydrogen bonds between two monomers, preventing dimerization process of PrP. The possible inhibition mechanism of PB2 and PB3 on PrP aggregation could provide useful information for drug development against prion diseases.
Communicated by Ramaswamy H. Sarma
Disclosure statement
No potential conflict of interest was reported by the author(s).