Insights from Molecular Docking and Dynamics Simulations of P2RX7-????Syn Complex

Abstract

Alpha-synucleinopathies, characterized by extracellular alpha-synuclein (Syn) accumulation and aggregation, have been linked to neurological disorders including Parkinsons disease (PD) and multiple system atrophy (MSA). Syn interacts with membrane proteins, phospholipids, and cholesterol, leading to membrane damage and inflammation. This interaction heightens the likelihood of Syn engaging with P2RX7, a non-selective cationic transmembrane receptor that is primarily overexpressed in immune and neural cells. Activation of P2RX7 by Syn is implicated in neuronal degeneration, potentially causing pore dilation and increased inflammation. However, the precise molecular mechanisms and binding sites for this interaction, as well as the conformational dynamics of P2RX7 in response to Syn, remain unclear. We attempted to elucidate the molecular mechanisms and binding sites for P2RX7-Syn interaction, by integrating the data curation, molecular docking, and molecular dynamics (MD) simulations coupled with structural analyses. We elucidated interactions between P2RX7 and the N-terminal domain (NTD) of Syn using cryo-EM structures of P2RX7 in both ATP-bound and unbound states and assessed how Syn influences P2RX7structural and functional dynamics. Initially, the analyses revealed that Syn interactomes are mainly involved in regulating mitochondrial homeostasis, while P2RX7 interactors are linked to receptor internalization and calcium transport. Molecular docking with six tools identified that Syn-NTD fragments preferentially bind to the proximal region of P2RX7 transmembrane domain. Microsecond all atom MD simulations in a POPS lipid bilayer showed significant atomic fluctuations, particularly in the head region, lower body, and large loop of P2RX7 cytoplasmic domain. Secondary structure analysis indicated unfolding in regions related to pore dilation and receptor desensitization. Further by contact-based and solvent accessibility analyses, along with protein structure network (PSN) studies, we identified crucial residues involved in Syn-P2RX7 interactions. This insight deepens our understanding of how Syn and P2RX7 interact, offering a detailed atomic view of the structural and functional changes that occur during these interactions. This understanding could advance our grasp of neurodegenerative diseases and be vital for devising future preventive and therapeutic strategies. Author summaryNeural homeostasis is crucial for neuron survival and function, with protein-protein interactions, particularly between Syn and P2RX7, playing a vital role. Accumulation of Syn can worsen neuronal damage through its interaction with P2RX7. Traditional biological experiments struggle with time-scale limitations, but advances in computational methods--like molecular dynamics (MD) simulations and protein structure network (PSN) analysis--allow detailed atomic-level study of these interactions. This study used these computational tools to explore the dynamics between Syn and P2RX7, aiming to uncover structural and functional changes relevant to protein interactions and neural damage. The findings contribute to understanding the dynamics of P2RX7-Syn interactions.