Protein segments with conformationally restricted amino acids can control supramolecular organization at the nanoscale.

Nanotechnology aims to design supramolecular systems able to perform complex functions. The selection of suitable building blocks and the control over their physicochemical properties play key roles in the chances of success. Here we summarize ideas that motivated our recent investigations focusing on the contribution of our results to the conformational control of the building blocks. We combined the structural versatility of naturally occurring polypeptides, the conformational features of a particular constrained class of non-natural restricted amino acids and the increasing computing power of modern molecular simulations to . Proteins adopting a β-helical conformation were used as scaffolds. Massive molecular dynamics simulations were used to detect the most flexible segments in each scaffold that preclude the formation of the nanostructure. Non-proteinogenic α-tetrasubstituted amino acids containing cyclic side chains (1-aminocycloalkanecarboxylic acids, Acc) were engineered to shift the population toward rigidified conformations of the selected fragments. Biasing the population away from conformational flexibility proved essential to the design of stable nanostructures.