Epitope region identification challenges of intrinsically disordered proteins in neurodegenerative diseases: Secondary structure dependence of α‐synuclein on simulation techniques and force field parameters

Abstract

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 β‐sheet conformation play a central role in the oligomerization and aggregation mechanisms of such proteins, including α‐synuclein, which is at the center of Parkinson's and Alzheimer's diseases. In this study, we simulated the monomeric α‐synuclein protein in an aqueous environment to evaluate its secondary structure properties, including β‐sheet propensity, and radius of gyration by replica exchange molecular dynamics simulations. We also obtained the molecular dynamics simulation trajectories of α‐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 α‐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 α‐synuclein in water. Herewith, we illustrate the challenges in epitope region identification of intrinsically disordered proteins in neurodegenerative diseases by current computer simulations.

Structures of the Wild-Type and S59L Mutant CHCHD10 Proteins Important in Amyotrophic Lateral Sclerosis–Frontotemporal Dementia

“…The secondary structure components and the probabilities per residue were calculated using the DSSP program and our own script. 29,30 We calculated the free energy change (ΔG) surface based on the R g and R EE values using the following relationship 31…”

Physicochemical Insights into the Role of Drug Functionality in Fibrillation Inhibition of Bovine Serum Albumin

“…Misfolding of proteins can generate highly ordered soluble amyloid fibrils or amorphous aggregates depending upon the followed pathway. − The misfolding process is driven by formation of transient intermediates, which promote fibrillation/aggregation depending upon the primary sequence of the protein and its environmental conditions. − Significant efforts are being made to address neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, diabetes, Creutzfeldt-Jakob, variant Creutzfeldt-Jakob, Gerstmann–Straussler–Scheinker, fatal familial insomnia, Kuru, and other diseases. , From the reports on extensively studied intrinsically disordered proteins (IDPs), ,,,− it is well established that amyloidogenic proteins show a generic feature of forming cross-β sheets due to folding aberrations. ,, The characteristic X-ray diffraction pattern of highly ordered amyloid fibrils has been shown to arise from formation of cross-β-sheet structures. ,,,− Recent studies on amyloid structures have come up with not only the expected cross-β amyloid structure but also diverse and complex structures . It has been observed that soluble amyloid fibrils specifically bind to thioflavin T (ThT) and Congo red molecules, whereas amorphous aggregates bind to 8-anilinonaphthalene-1-sulfonic acid (ANS). − …”

“…Other than the intrinsically disordered proteins, ,,,, globular proteins also lead to formation of aggregates/fibrils upon protein-folding aberrations. ,− Literature reports describe the process of aggregation/fibrillation of serum albumin under different conditions of concentration and temperature. ,− Serum albumin is a carrier protein for exogenous and endogenous ligands, which upon aggregation/fibrillation affects the blood circulatory system. ,, Bovine serum albumin (BSA) consists of α-helices along with some turns and random coils. ,, Upon aggregation/fibrillation, 40% increase in the β-sheet structure is observed in the protein, which retains a significant α-helical structure as well …”

Secondary structure dependence of amyloid‐β(1–40) on simulation techniques and force field parameters

“…We recently studied the challenges in epitope region identification of α‐synuclein that is an intrinsically disordered protein at the center of neurodegenerative diseases (Mandaci et al., 2020). Those investigations showed that the epitope region of α‐synuclein depends highly on the chosen simulation technique, simulation protocol, and force field parameter set.…”