Benchmark of force fields to characterize the intrinsically disordered R2-FUS-LC region

ABSTRACTAmyloid fibrils formations are involved in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Amyotrophic Lateral Sclerosis (ALS) and others. The proteins associated with the formation of amyloid fibrils are Intrinsically Disordered Proteins (IDP) in the unbound state. Nevertheless, this type of proteins can self-aggregate and form cross-β amyloid fibrils structures at physiological condition.Due to the flexibility of these IDPs, no single experimental approach could completely characterize this system, especially in the unbound state. All-atom molecular dynamics (MD) simulations could be used to study the conformational ensemble of IDPs. Unfortunately, force fields (FF) and water models (WM) were developed to simulate one structure of folded proteins. Recently, several FF/WM were improved to properly generate conformational ensembles of IDP. However, it is unknown if the force fields (FF) can properly reproduce the behavior of IDP and also self-aggregate in cross-β amyloid fibrils structures.In this paper, we will focus of the R2 region of the FUS-LC domain (R2-FUS-LC region) which is an Intrinsically Disordered Region (IDR) of 16 residues in the unbound state but forms cross-β fibrils in the bound state. For the R2-FUS-LC region, we benchmarked thirteen commonly used FFs for studying IDPs. We show that CHARMM36m (updated in 2021) with mTIP3P water model performs the best to generate extended structures and cross-β amyloid fibril.