Furthermore, both structures share an H-bond pattern in which two amino H atoms interact with two carboxylic oxygen atoms of two distinct dipeptides, with the third interacting with a water molecule inside the channel. The latter interaction was proven in the case of compound 1 by studying a model in which the water molecules were not masked. Weak hydrophobic interactions established by the Phe and Nle side chains help to hold together the tubes through the establishment of steric zippers, which is a common feature for amyloids that can stabilize hydrogels formed by hydrophobic short peptides with Leu and Phe. Interestingly, not only replacement of Leu with Nle enables the formation of nanotubes with varying diameter, but also it enables formation of steric zippers that stabilize the hydrogel of 3, while such a feature is absent in the analog Phe-Leu, which fails to gel under analogous conditions. 28 A higher degree of similarity is instead found between heterochiral 4 and its analog with Leu instead of Nle, as both displayed a metastable character with crystals arising from the hydrogel over time. The packing in both cases shows distinctive amphipathic layers within a monoclinic system (space group C2), with water layers parallel to the shortest b axis (Fig. ). The hydrophilic amide-rich region is formed by four dipeptides, whereas the side chains are gathered in the hydrophobic region forming weak interactions and excluding the water molecules. The disordered water molecules can be considered enclosed within channels and they create hydrogen XRD analyses were then performed on xerogels to verify whether a similar packing mode could be found in the gel and crystal phases (Fig. and ESI Section S10). Compound 1 displayed strikingly similar patterns in the two phases that were reminiscent of those displayed by Phe-Phe xerogels and crystals, which also assembled in a similar fashion giving rise to water channels whose cavity was defined by 6 peptide molecules arranged head-to-tail. By contrast, the calculated X-ray powder diffraction (XRPD) pattern from single crystal data of 3 was different from the experimental XRPD pattern of the corresponding xerogel, which, instead, was similar to that of compound 1. We hypothesize that the water channels defined by 4 peptide molecules of 3 found in the crystal structure are not representative of the packing mode in the gel phase that, instead, could display water channels defined by 6 peptide molecules similar to 1, and to Phe-Phe. Analogous was the case for compounds 2 and 4, whose calculated patterns in the crystal phase were remarkably different from those of the other compounds, and from the experimental pattern of the xerogel of 2, which, again, showed similarities with that of 1. It is possible that in the hydrated gels, compounds 1-3 pack similarly to form water channels defined by 6 peptide molecules, as supported by similar Raman spectra too. It is worth noting that D-Phe-L-Phe, which displays a similar packing mode, was found to form nanotubes defined by two peptide layers and with an outer diameter of 4.3 nm, which matches the TEM measurements for individual fibrils of compounds 1-4 shown in Figure . Unfortunately, it was not possible to collect the XRPD pattern of 4, which inevitably crystallized under self-assembly conditions, analogously to D-Phe-L-Leu. 28