All-atom Simulations of the Phase Behavior of P1 Domain of α-Synuclein

Abstract

Biomolecular condensate formation within the cell is regulated via weak multivalent interactions between intrinsically disordered proteins (IDPs). Recent evidences suggest the formation of such condensates prior to pathogenic aggregates. The aggregated states of the presynaptic intrinsically disordered protein, α-Synuclein have long been associated with Parkinson’s disease. Although α-Synuclein aggregation is majorly driven by the non-amyloid β- component (NAC) domain, a 7-residue sequence known as P1 (residues 36-42) within the flanking N-terminal region has emerged as the ‘master-controller’ of α-Synuclein function and aggregation. In order to gain molecular insight into the properties of the P1 domain, here we investigate its phase separation characteristics using all-atom molecular dynamics simulations at varying temperatures. Our results indicate that P1 is able to phase separate above a lower critical solution temperature (LCST). P1 chains remain highly dynamic in the condensed phase and their condensation is driven by weak multi-chain hydrophobic interactions between the residues. In particular, it is found that Y39 forms stable contacts with different residue pairs within the dense phase. Our study demonstrates that P1 sequence likely plays a crucial role in driving condensate formation of the full length α-Synuclein protein