236: Conformational dynamics and transitions in the formation of dimeric and trimeric sub-self-assemblies of helical peptoids

Abstract: Peptoids are structural isomers of polypeptides in which the side chain is attached to the amide nitrogen rather than the α-carbon. This backbone modification eliminates backbone hydrogen-bond donors, thereby increasing conformational flexibility and enhancing proteolytic stability relative to polypeptides. Owing to their tunable side-chain chemistry and structural versatility, peptoids have attracted significant interest in biomedicine, electronics, and catalysis. Given the central role that side-chain chemistry plays in peptoid self-assembly, accurate parametrisation of side-chain dihedral potentials is essential for reproducing experimentally observed cis–trans free energy differences. To address this, we employ the Systematic and Extensible force field for Peptoids (STEP) framework, which provides peptoid-specific parameters for over 70 side chains built upon GAFF2 and is extendable to new chemistries. Using this force field, we investigate the conformational dynamics of cis–trans isomerization in a helical peptoid that favours a cis-dominated self-assembled structure in aqueous solution. To further elucidate the intermolecular interactions governing cooperative association, we characterise the formation and metastability of helical dimers and trimers. Analysis of these sub-assemblies provides insight into backbone packing and side-chain orientation during early stages of self-assembly. Local interaction energetics within these oligomeric states offer mechanistic insight into nucleation, although full growth toward higher-order assemblies necessarily involves many-body effects and collective thermodynamic and kinetic reorganisation.