Structural analyses and force fields comparison for NACore (68-78) and SubNACore (69-77) fibril segments of Parkinson's disease.

The α-synuclein fibrils are a pathological hallmark of Parkinson's disease (PD) and are abundant in the brains of PD patients. These amyloid fibrils can aggregate into distinct polymorphism under different physical conditions. Therefore, these different fibril polymorph formations should be considered in drug design studies targeting amyloid fibrils. Recently, the atomic structures of two small fibril segments of α-synuclein, named NACore (68-78) and SubNACore (69-77), have been crystallized. These segments are critical for cytotoxicity and fibril formation. Therefore, elucidation of interface interactions between pair sheets of the NACore and SubNACore is significant for the clarification of the mechanism of fibril formation in PD. In this context, molecular dynamics (MD) simulation technique is a convenient tool to investigate interface interactions of these segments at the atomic level. However, the accuracy of these simulations depends on the utilized force fields. Therefore, we have tested the dependence of interface interactions and stabilities of these small amyloid fibrils on various force fields. From the results of triple long (100 ns) MD simulations, we inferred for the stability investigations of the NACore and SubNACore that CHARMM27 and GROMOS53A6 are the most convenient force fields whereas AMBER99SB-ILDN is the most unfavorable one. Consequently, it is expected that our findings will guide the selection of the appropriate force field for simulations between these segments and possible inhibitors of this disease.