Binary and Ternary Complexes of Cucurbit[8]uril with Tryptophan, Phenylalanine, and Tyrosine: A Computational Study

[Image: see text] Selective binding of amino acids, peptides, and proteins by synthetic molecules and elucidation of the geometry and dynamics of the resulting complexes and their strengths are active areas of contemporary research. In recent work, we analyzed via molecular dynamics (MD) simulations the complexes formed between cucurbit[7]uril (CB7) and three aromatic amino acids: tryptophan (W), phenylalanine (F), and tyrosine (Y). Herein, we continue this line of research by performing MD simulations lasting 100 ns to investigate the formation, stabilities, binding modes, dynamics, and specific host–guest noncovalent interactions contributing to the formation of the binary (1:1) and ternary (2:1) complexes in aqueous solution between W, F, and Y amino acids and cucurbit[8]uril (CB8). All complexes were found to be stable, with the binding in each complex dominated by one mode (except for the F–CB8 complex, which had two) characterized by encapsulation of the aromatic side chains of the amino acids within the cavity of CB8 and the exclusion of their ammonium and carboxylate groups. Using the molecular mechanics/Poisson–Boltzmann surface area method to estimate the individual contributions to the overall free energies of binding, results revealed that the key role is played by the amino acid side chains in stabilizing the complexes through their favorable van der Waals interactions with the CB8 cavity and the importance of favorable electrostatic interactions between the carbonyl portal of CB8 and the ammonium group of the amino acid. Visual analysis of structures of the ternary complexes indicated the presence of π–π stacking between the aromatic side chains of the included amino acids. The insights provided by this work may be of value for further efforts aiming to employ the recognition properties of CB8 toward amino acids in applications requiring more elaborate recognition of short peptides and proteins.