Effect of Organochloride Guest Molecules on the Stability of Homo/Hetero Self-Assembled α,γ-Cyclic Peptide Structures: A Computational Study Toward the Control of Nanotube Length

We present here a molecular dynamics study on peptide nanotubes composed of <i>cis-</i>3-aminocyclohexanecarboxylic acid-(γ-Ach) or <i>cis-</i>3-aminocyclopentanecarboxylic acid (γ-Acp)-based α,γ-cyclohexapeptides and also on those formed by heterodimeric pairs from a combination of the two aforementioned peptides (γ-Ach/Acp), which is the first time that a self-assembling cyclic peptide nanotube composed of heteromeric units is investigated. The main advantage of these types of nanotube is that they have a partially hydrophobic inner cavity, a property that makes them very exciting alternatives to classical nanotubes. In an effort to analyze the fine details of these ensembles, we investigated the dynamical behavior of model dimeric structures that mimic the fundamental repeating structural motif of longer nanotubes. Despite the structural analogy of the β-sheet interaction, our results suggest that extrapolation of the information obtained from those “capped” dimers to nanotube properties has some limitations because several significant differences have been found between the two systems. This finding is not only relevant for α,γ-cyclic peptide nanotubes but also shows that special care should also be taken when considering other related peptide nanotubes in which N-methylated dimers are used to obtain information about the stability and formation of the nanotubes. The structural and dynamical behavior of dimers and nanotubes in nonpolar (chloroform) and polar protic solvents (water) has been analyzed using state-of-the-art theoretical methods. A marked destabilizing effect on the structure was observed in aqueous solution for all systems studied, suggesting that most of the water molecules that compete for the hydrogen bonds are those that occupy the internal cavity. We show that the introduction of organochloride molecules within the dimers and nanotubes is stabilized in water, and this property opens the door to a large number of possible future applications that are an important challenge in the field of molecular self-assembly, such as in drug delivery processes to control nanotube length by means of appropriate guests. A precise control of the nanotube length can be envisaged from the MD simulations of the encapsulation of 1,2-bis­[2-(2,2,2-trichloroethoxy)­ethoxy]­ethane inside its inner cavity, opening a very interesting possibility in this area