Structural and energetic effects in the molecular recognition of acetylated amino acids by 18-crown-6

Absolute 18-crown-6 (18C6) binding affinities of four protonated acetylated amino acids (AcAAs) are determined using guided ion beam tandem mass spectrometry techniques. The AcAAs examined in this work include: N-terminal acetylated lysine (N(α)-AcLys), histidine (N(α)-AcHis), and arginine (N(α)-AcArg) as well as side chain acetylated lysine (N(ε)-AcLys). The kinetic-energy-dependent cross sections for collision-induced dissociation (CID) of the (AcAA)H(+)(18C6) complexes are analyzed using an empirical threshold law to extract absolute 0 and 298 K (AcAA)H(+)-18C6 bond dissociation energies (BDEs) after accounting for the effects of multiple collisions, kinetic and internal energy distributions of the reactants, and unimolecular dissociation lifetimes. Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the AcAAs as well as the proton bound complexes of these species, (AcAA)H(+)(18C6), at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31 G* and M06/6-311+G(2d,2p)//B3LYP/6-31G* levels of theory. For all four (AcAA)H(+)(18C6) complexes, loss of neutral 18C6 corresponds to the most favorable dissociation pathway. At elevated energies, products arising from sequential dissociation of the primary CID product, H(+)(AcAA), are also observed. Protonated N(α)-AcLys exhibits a greater 18C6 binding affinity than other protonated N(α)-AcAAs, suggesting that the side chains of Lys residues are the preferred binding sites for 18C6 complexation to peptides and proteins. N(α)-AcLys exhibits a greater 18C6 binding affinity than N(ε)-AcLys, suggesting that binding of 18C6 to the side chain of Lys residues is more favorable than to the N-terminal amino group of Lys.