A study of alpha-synuclein and poly(<i>N</i>-isopropylacrylamide) complex formation through detailed atomistic simulations.

Abstract

This work presents an investigation of the influence of poly(<i>N</i>-isopropylacrylamide) (PNIPAM) polymer on the structural dynamics of intrinsically disordered alpha-synuclein (α-syn) protein, exploring the formation and intricate features of the resulting α-syn/PNIPAM complexes. Using atomistic molecular dynamics (MD) simulations, our study analyzes the impact of initial configuration, polymer molecular weight, and protein mutations on the α-syn and the α-syn/PNIPAM complex. Atomistic simulations, of a few μs, of the protein/polymer complex reveal crucial insights into molecular interactions within the complex, emphasizing a delicate balance of forces governing its stability and structural evolution. Our findings indicate that PNIPAM polymer engages in significant non-polar interactions with the non-amyloid component (NAC) region of α-syn, which plays a crucial role in fibril formation, under various conditions such as the mutations in the protein structure and polymer chain length. Especially the PNIPAM polymer with a 40mer monomer exhibits a stabilizing effect on the structural properties of the protein, reducing intramolecular interactions that contribute to misfolding. These findings, which delve into protein/polymer interactions, hold promise as potential guidance for therapeutic strategies in various neurodegenerative disorders.