Stabilizing structures of cysteine-containing crystals with respect to variations of temperature and pressure by immobilizing amino acid side chains

Abstract

In a series of recent publications, the crystals of L- and DL-cysteine were shown to undergo multiple phase transitions upon variation of temperature and pressure. All these transitions are related to rotation of the amino acid side chain. Accordingly, cysteine-containing crystal structures should be stabilized with respect to phase transitions by measures that reduce the mobility of the side chain in the crystalline environment. In the present work, we show that this can be achieved by increasing the significance of the side chain –SH group as a participant in intermolecular hydrogen bonds, either by N-acetylation, which removes the strong –NH₃⁺ donor of cysteine and leaves a system without strong charge-assisted interactions, or by co-crystallization with an acid (oxalic acid) that converts the amino acid to a cation and itself forms a strong anion H-bond acceptor, thus boosting the importance of potential –SH donors. The crystal structures of the three compounds N-acetyl-L-cysteine, DL-cysteinium semioxalate, and bis(DL-cysteinium) oxalate have thus been studied with variation of temperature and pressure. Cooling down to 4 K and increasing pressure up to 9.5 GPa did not result in any structural phase transitions in N-acetyl-L-cysteine and bis(DL-cysteinium) oxalate. In case of DL-cysteinium semioxalate, increasing pressure caused a phase transition at a much higher pressure (∼6 GPa), compared to the ranges of pressure-induced phase transitions observed earlier for both monoclinic and orthorhombic L-cysteine (2.5–3.9 GPa and 1.1–2.5 GPa, respectively) or DL-cysteine (0.1–5 GPa). This phase transition had a large hysteresis, so that the reverse transformation on decompression was observed at ∼3.7 GPa only, and was accompanied by a change in molecular conformations, as well as by the reorganization in the N–H⋯O hydrogen bonds in the crystal structure.