Molecular Mechanism of Self-Assembly of Aromatic Oligoamides into Interlocked Double-Helix Foldamers

Foldamer, inspired by the structures and functions of biopolymers, is defined as an artificial molecular architecture that can fold into a three-dimensional structure in solution and has been a growing and active field in supramolecular chemistry. The central issue in foldamer science is to understand how the primary sequence of oligomer folds into conformationally ordered structures as well as how individual subunits self-associate into assembly. For duplex structures, these two issues are always interrelated and inseparable with each other. Although the emergence of new foldamer keeps growing, the detailed mechanism remains elusive. On the basis of an artificially synthesized arylamide oligoamide foldamer with its crystal structure available, we constructed a set of four foldamers with a similar backbone but different substituents and aimed at dissecting the folding and self-association mechanisms of a double-helical foldamer with computations. Using molecular simulations at a microsecond time scale, we observed very consistent processes of the spontaneous self-assembly of two single-helical motifs into an entwined complex. Our results reveal that aggregation of two single-helical motifs driven by extensive π–π interactions is energetically favorable and that this spontaneous self-assembly proceeds through an “unwinding–threading–rewinding” mechanism. The detailed mechanisms about the folding and self-assembly in an aromatic oligoamide foldamer we present here disclose how the sequence is associated with a well-ordered three-dimensional structure at atomic level and therefore may have implications for designing new foldamers with versatile functions.