The ability of Torin 1 COMPcc to bind various fatty acid molecules is directly related to its physicochemical properties. A key role in the electrostatic fixation of polarized ligands inside the aliphatic channel is played by the Gln54 ring system. The Gln54 residue belongs to a four amino acid motif that is conserved among the pentameric thrombospondins. Gln54 is situated at position d of the characteristic heptad repeat n, which is unusual, since the a and d positions are normally occupied by hydrophobic residues. The hydrogen bonds of the Gln54 ring are arranged into a funnel-like manner, such that the partial positive charges on the amide nitrogens are oriented towards the bottom of the funnel and the partial negative charges on the carbonyl oxygens towards the top. This creates a dipole, which is parallel to the dipole moment of the a-helices. The positivelycharged bottom of the funnel can act as a trap for negatively charged ions, as demonstrated in the native structure of COMPcc where a chloride ion is bound. Interestingly, it was shown that the melting point of COMPcc was increased from 73uC to 104uC when Gln54 was mutated to a Leu residue. This implies an evolutionary advantage of the less thermostable wild type COMPcc over the Q54L mutant and suggests an additional function of the glutamine residues inside the pentameric channel. This decrease in thermal stability can be compensated by ligand binding: the midpoint transition temperature of unfolding increased by 2uC with benzene or cyclohexane bound in the channel, by 8uC when vitamin D3 and by 10uC with 18:1 trans-9 elaidic acid. Two additional core residues, all at the d position of the heptad repeat play a crucial role in the binding of diverse cargo elements. Firstly, Met33 at the N-terminal opening of the COMPcc channel forms a gating pore with a diameter of 3.4 A˚. The CH3- moieties face each other and establish strong van der Waals contact forces. In contrast the polarizable sulphur components of the thioether are oriented towards the inner core of the pentameric channel. Therefore, one can assume that in order for any ligand to enter the COMPcc channel, the gate has to open thereby permitting access. This assumption is underlined by changes within the helical backbone at the very N-terminus. Secondly, Thr40, a subsequent residue in the next heptad repeat, forms interhelical hydrogen bonds between its bhydroxyl group and the amide group of Asn41. Previous work has shown, that the side chains of the individual Thr40 residues undergo significant re-orientations during ligand binding. In addition to re-orientation, it has also been shown that between the concentric Thr40/Asn41 arrangement and Leu37, a water chamber is formed that contains up to five water molecules inside the pentameric channel. Comparing wild type COMPcc with COMPcc in complex with vitamin D3, myristic acid, palmitic acid and stearic acid reveals an interesting pattern. Whereas apo-COMPcc has water molecules lined up along the full length of the channel, the complex structures only contain water in the water chamber. An interesting result is observed in the structure of the COMPcc-palmitic acid complex. In this case, the water chamber is empty and instead a cloud of water molecules is surrounding a second bent palmitic acid ligand that is located outside the entrance to the channel. This suggests that the release of channel waters plays a key role in facilitating the binding of fatty acids into the pentameric COMPcc channel.