The Origin of Selectivity in the Complexation of N-Methyl Amino Acids by Tetraphosphonate Cavitands

Abstract

We report on the eligibility of tetraphosphonate resorcinarene cavitands for the molecular recognition of amino acids. We determined the crystal structure of 13 complexes of the tetraphosphonate cavitand Tiiii[H, CH3, CH3] with amino acids. (1)H NMR and (31)P NMR experiments and ITC analysis were performed to probe the binding between cavitand Tiiii[C3H7, CH3, C2H5] or the water-soluble counterpart Tiiii[C3H6Py(+)Cl(-), CH3, C2H5] and a selection of representative amino acids. The reported studies and results allowed us (i) to highlight the noncovalent interactions involved in the binding event in each case; (ii) to investigate the ability of tetraphosphonate cavitand receptors to discriminate between the different amino acids; (iii) to calculate the Ka values of the different complexes formed and evaluate the thermodynamic parameters of the complexation process, dissecting the entropic and enthalpic contributions; and (iv) to determine the solvent influence on the complexation selectivity. By moving from methanol to water, the complexation changed from entropy driven to entropy opposed, leading to a drop of almost three orders in the magnitude of the Ka. However, this reduction in binding affinity is associated with a dramatic increase in selectivity, since in aqueous solutions only N-methylated amino acids are effectively recognized. The thermodynamic profile of the binding does not change in PBS solution. The pivotal role played by cation-π interactions is demonstrated by the linear correlation found between the log Ka in methanol solution and the depth of (+)N-CH3 cavity inclusion in the molecular structures. These findings are relevant for the potential use of phosphonate cavitands as synthetic receptors for the detection of epigenetic modifications of histones in physiological media.

Entropy‐Driven Cooperativity in the Guest Binding of an Octaphosphonate Bis‐cavitand

“…73, 1112.73, 1121.73, and 2206.44, which correspond The hydrogen-bonding interaction of water molecules with oxygen atoms in the P=Ob onds reduces the electron density of the phosphorus atoms, which causes downfield shifts in the 31 PNMR signals. [12] Therefore, the strength of the hydrogenbondingi nteractions of water molecules can be evaluated through the 31 PNMR shifts. The phosphonate signals of 1a, 1b,a nd 2 appeared at 10.6, 9.19, and 8.97 ppm, respectively ( Figure S25 in the Supporting Information).…”

Supramolecular Chemistry Targeting Proteins

“…The pivotal role of methylated cationic amino acid residues is not limited to calixarenes but is also observed for other cavitands. 36 …”

Synthetic Receptors for the Recognition and Discrimination of Post‐Translationally Methylated Lysines

“…The affinity for the N + −Me group originates from three types of non‐covalent interactions between host and guest: 1) cation ⋅⋅⋅ dipole interactions (N + ⋅⋅⋅ O=P), 2) cation ⋅⋅⋅ π interactions of the methyl group with the aromatic cavity and 3) two hydrogen bonds between the two nitrogen protons and two adjacent P=O bridges. These features are also found in the X‐ray structures of respective tetraphosphonates with monomethyllysines, as reported by Dalcanale and co‐workers, namely, receptor 25 in complex with methyllysine ⋅ 2 HCl ⋅ 6.4 CF 3 CH 2 OH ⋅ H 2 O (CSD code: OJISEH; Scheme ) and 26 in complex with methyllysine ⋅ HCl ⋅ H 2 O (CSD code: IKOZUF).…”