Amino Acid Influence on Copper Binding to Peptides: Cysteine Versus Arginine

Matrix assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) and theoretical calculations [density functional theory (DFT)] were utilized to investigate the influence of cysteine side chain on Cu+ binding to peptides and how Cu+ ions competitively interact with cysteine (−SH/SO3H) versus arginine. Results from theoretical and experimental (fragmentation reactions) studies on [M + Cu]+ and [M + 2Cu − H]+ ions suggest that cysteine side chains (−SH) and cysteic acid (−SO3H) are important Cu+ ligands. For example, we show that Cu+ ions are competitively coordinated to the −SH or SO3H groups; however, we also present evidence that the proton of the SH/SO3H group is mobile and can be transferred to the arginine guanidine group. For [M + 2Cu − H]+ ions, deprotonation of the −SH/SO3H group is energetically more favorable than that of the carboxyl group, and the resulting thiolate/sulfonate group plays an important role in the coordination structure of [M + 2Cu − H]+ ions, as well as the fragmentation patterns