Evolution of the Free Energy Landscapes of n-Alkane Guests Bound within Supramolecular Complexes

Confinement within nanoscale spaces can dramatically alter the ensemble of conformations flexible species explore. For example, chaperone complexes take advantage of confinement to fold misfolded proteins, while viral capsids transport genomic materials in tight packings. Here we examine the free energy landscapes of n-alkanes confined within supramolecular dimeric complexes of deep-cavity cavitand octa-acid, which have been experimentally demonstrated to force these chains with increasing length to adopt extended, helical, hairpin, and spinning top conformational motifs, using molecular simulations. Alkanes up to n-docosane in both vacuum and water predominantly exhibit a free energy minimum for elongated conformations with a majority of trans dihedrals. Within harmonically sealed cavitand dimers, however, the free energy landscapes as a function of the end-to-end distance between their terminal methyl units exhibit minima that evolve with the length of the alkane. Distinct free energy basins are observed between the helical and hairpin motifs and between the hairpin and chicane motifs whose relative stability changes with the number of carbons in the bound guest. These changes are reminiscent of two state-like protein folding, although the observed alkane conformations confined are more insensitive to temperature perturbation than proteins are. While the chicane motif within the harmonically sealed dimers has not been observed experimentally, this conformation relaxes to the observed spinning top motif once the harmonic restraints are released for the complexes in aqueous solution, indicating that these motifs are related to one another. We do not observe distinct minima between the confined extended and helical motifs, suggesting these conformers are part of a larger linear motif family whose population of gauche dihedral angles grows in proportion to the number of carbons in the chain to ultimately form a helix that fits the alkane within the complex.