Epitope Region Identification Challenges of Intrinsically Disordered Proteins in Neurodegenerative Diseases: Secondary Structure Dependence of α‐Synuclein on Simulation Techniques and Force Field Parameters

Due to fast aggregation processes of many disordered proteins in neurodegenerative diseases, it is difficult to study their epitope regions at the monomeric and oligomeric levels. Computer simulations complement experiments and have been used to identify the epitope regions of proteins. Residues that adopt beta-sheet conformation play a central role in the oligomerization and aggregation mechanisms of such proteins, including alpha-synuclein, which is at the center of Parkinson's and Alzheimer's diseases. In this study, we simulated the monomeric alpha-synuclein protein in an aqueous environment to evaluate its secondary structure properties, including beta-sheet propensity, and radius of gyration by replica exchange molecular dynamics simulations. We also obtained the molecular dynamics simulation trajectories of alpha-synuclein that were conducted using various force field parameters by the David E. Shaw group. Using these trajectories, we calculated the impacts of force field parameters on alpha-synuclein secondary structure properties and radius of gyration values and obtained results are compared with our data from REMD simulations. This study shows that the chosen force field parameters and computer simulation techniques effect the predicted secondary structure properties and radius of gyration values of alpha-synuclein in water. Herewith, we illustrate the challenges in epitope region identification of intrinsically disordered proteins in neurodegenerative diseases by current computer simulations.