Sampling the Conformational Space of the Parkinson's Disease Associated Protein Alpha-Synuclen

Aggregation of the protein Alpha-synuclein into amyloid fibrils is linked to the neurodegenerative condition Parkinson’s Disease. This aggregation pathway is not fully understood, and the intrinsically disordered (IDP) nature of the protein adds to its complexity. In the present study, the conformational space of Alpha-synuclein was explored using Molecular Dynamics (MD) simulations, utilizing the Associative Memory, Water Mediated, Structure and Energy Model (AWSEM-MD). To optimize AWSEM-MD for IDP dynamics, reductions to parameters of the model were tested in monomer simulations. From these, a set of parameters were chosen based on protein radius of gyration and secondary structure. Tetramer simulations were run with four chains using enhanced sampling techniques under standard AWSEM-MD parameters, reduced parameters selected from the previous monomer simulations, and an additional reduced parameter group with two point mutations. Trajectories from the tetramer simulations were analyzed for radius of gyration and secondary structure, and representative conformations were selected through clustering. Tetramers were observed showing interactions between termini resulting in a variety of conformations, with the most compact potentially resembling an experimentally reported spherical tetramer that resists aggregation. Parameter reduction produced the greatest beta sheet propensity, and a trimer with a free monomer was observed in the mutant group. This project was completed with contributions from Aram Davtyan from the Center for Theoretical Biological Physics, Rice University.