3.3.2. Binding Sites

An analysis of complexes of calix[6]arenes with amino acids reveals that several preferred binding sites can be identified. The most straightforward situation arises for the *wc* conformer, where for all forty cases (twenty amino acids and two calixarenes), the preferred binding site is on the top of the molecule, i.e., where all the hydroxy groups reside. For this conformer the hole is smaller because of the flattened shape–one should note that two phenyl rings (third and sixth according to Figure 2) are placed approximately in a position of a "shifted sandwich", which turns out to be the optimal one for two benzene molecules [116].

For the *al* conformer, two preferred binding sites can be identified, which both have a form of a cavity because of a specific orientation of calixarene units for this conformer: in comparison to the *pc* case three units are turned upside down. The most popular cavity is the cavity created by the third, fourth, and fifth units in the case of CX, but in some cases, the second cavity created by the remaining rings is used by amino acid guests. The latter situation occurs for: Phe-CX, Phe-BCX, Trp-CX, and Tyr-BCX. It should be noted that for all these cases, the amino acid contains an aryl group.

For the *pc* conformer, three docking places can be identified. One of these places is the top of the cone, while the other–the bottom cavity. If a larger amino acid occupies the cone, its residual part is usually placed along the groove made of units two and three, i.e., between two semi-circles, and in some cases, the groove becomes the only docking site (see the complex with Tyr) without attaching to the hydroxy-rich cone part at all. In the latter case, the guest molecule is, as a rule, shifted from the center of the cavity and resides on one side of the semi-circle, but in several cases (for larger molecules) both cavities are used. Somewhat surprisingly, the top position is preferred for the calix[6]arene host, while inclusion complexes are more common for the hexa*p*-*tert*-butylcalix[6]arene, in spite of space obstacles on the calixarene rim for the latter case. Only Ile, Lys, Pro, and Val amino acids are docked in the cavity for the *pc*-CX. In all these cases one side of the cavity, created by units third to fifth, is used. Because of this position of the guest molecule, the structure of the six-member H-bond ring is often unharmed by the complexation, which can be also seen by the O··· H distance in the H-bonds, which remains within the range 1.63–1.7 Å after the complexation. The distance between the closest hydrogen atoms from the methylene linkers (CH2-5 and CH2-2) become larger by 0.2–0.3 Å for Lys and Val, which are the largest amino acids from this set, while it is enlarged by only 0.1 Å for Ile and becomes 0.1 Å smaller for the most compact Pro guest. For the hexa-*p*-*tert*-butylcalix[6]arene host, a majority of amino acids choose the cavity as the preferred binding site and seven only are attached to the hydroxy-decorated top (Asn, Cys, Gly, HisD, HisE, Ser, and Thr).

The Cartesian geometries of all the complexes are listed in the Supplementary Information.
