Determination of Relative Stabilities of Metal-Peptide Bonds in the Gas Phase.

Understanding binding site preferences in biological systems as well as affinities to binding partners is a crucial aspect in metallodrug development. We here present a mass spectrometry-based method to compare relative stabilities of metal-peptide adducts in the gas phase. Angiotensin 1 and substance P were used as model peptides. Incubation with isostructural N-heterocyclic carbene (NHC) complexes of Ru ^II , Os ^II , Rh ^III , and Ir ^III led to the formation of various adducts, which were subsequently studied by energy-resolved fragmentation experiments. The gas-phase stability of the metal-peptide bonds depended on the metal and the binding partner. Of the four complexes used, the Os ^II derivative bound strongest to Met, while Ru ^II formed the most stable coordination bond with His. Rh ^III was identified as the weakest peptide binder and Ir ^III formed peptide adducts with intermediate stability. Probing these intrinsic gas-phase properties can help in the interpretation of biological activities and the design of site-specific protein binding metal complexes.
(© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)