A theoretical and experimental case study of the hydrogen bonding predilection of S-methylcysteine

S-containing amino acids can lead to two types of local NH center dot center dot center dot S interactions which bridge backbone NH sites to the side chain to form either intra- or inter-residue H-bonds. The present work reports on the conformational preferences of S-methyl-l-cysteine, Cys(Me), using a variety of investigating tools, ranging from quantum chemistry simulations, gas-phase UV and IR laser spectroscopy, and solution state IR and NMR spectroscopies, on model compounds comprising one or two Cys(Me) residues. We demonstrate that in gas phase and in low polarity solution, the C- and N-capped model compound for one Cys(Me) residue adopts a preferred C5-C6 gamma conformation which combines an intra-residue N-H center dot center dot center dot O=C backbone interaction (C5) and an inter-residue N-H center dot center dot center dot S interaction implicating the side-chain sulfur atom (C6 gamma). In contrast, the dominant conformation of the C- and N-capped model compound featuring two consecutive Cys(Me) residues is a regular type I beta-turn. This structure is incompatible with concomitant C6 gamma interactions, which are no longer in evidence. Instead, C5 gamma interactions occur, that are fully consistent with the turn geometry and additionally stabilize the structure. Comparison with the thietane amino acid Attc, which exhibits a rigid cyclic side chain, pinpoints the significance of side chain flexibility for the specific conformational behavior of Cys(Me).