In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes.

Carlos Navarro-Paya,Alfonso De Simone,Maximo Sanz-Hernandez

doi:10.3390/life10060098

Abstract

The membrane binding by α-synuclein (αS), a presynaptic protein whose aggregation is strongly linked with Parkinson’s disease, influences its biological behavior under functional and pathological conditions. This interaction requires a conformational transition from a disordered-unbound to a partially helical membrane-bound state of the protein. In the present study, we used enhanced coarse-grained MD simulations to characterize the sequence and conformational determinants of the binding to synaptic-like vesicles by the N-terminal region of αS. This region is the membrane anchor and is of crucial importance for the properties of the physiological monomeric state of αS as well as for its aberrant aggregates. These results identify the key factors that play a role in the binding of αS with synaptic lipid bilayers in both membrane-tethered and membrane-locked conformational states.

Highlights

Introduction αSynuclein is a 14 kDa protein that is highly abundant in the brain, where it localizes predominantly at the synaptic terminals [1,2,3]
In order to study the interaction of αS with synaptic-like membranes employed in previous experimental studies [40], we simulated a membrane composed of DOPE, DOPS and DOPC lipids in a 5:3:2 (w/w) ratio (167 lipid molecules in total) and the acetylated N-terminal region of αS
DOPE:DOPS:DOPC lipid bilayers, we performed a series of CG molecular dynamics (MD) simulations using a modified version of the Martini 3 force field

Summary

Introduction

Introduction αSynuclein (αS) is a 14 kDa protein that is highly abundant in the brain, where it localizes predominantly at the synaptic terminals [1,2,3]. The aggregation of αS is associated with the formation of Lewy Bodies in Parkinson’s disease (PD) and in other synucleinopathies [4,5,6,7,8]. The main body of evidence indicates that it has a role in regulating the trafficking of synaptic vesicles (SVs) [15,16,17,18], including a chaperone role in SNARE formation via an interaction with VAMP-2 at the surface of SVs [15,16,18]. The majority of the suggested functions of αS involve the crucial step of binding to cellular membranes, a process that is tightly regulated in vivo [26], and that affects the rate of αS aggregation [27,28,29] and the toxicity of its aggregates [22,30]

Methods

Results

Conclusion