A comparative computational study of matrix-peptide interactions in MALDI mass spectrometry: the interaction of four tripeptides with the MALDI matrices 2,5-dihyroxybenzoic acid, α-cyano-4-hydroxy-cinnamic acid and 3,5-dihyroxybenzoic acid

The mechanisms of matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) has been investigated by focusing on the interaction between MALDI matrices and several tripeptides. 2,5-dihyroxybenzoic acid, alpha-cyano-4-hydroxy-cinnamic acid and 3,5-dihyroxybenzoic acid were studied as MALDI matrices interacting with four tripeptide sequences taken from bovine insulin: glutamic acid-arginine-glycine, glutamine-histidine-leucine, serine-histidine-leucine and threonine-proline-lysine. Molecular dynamics/simulated annealing calculations followed by geometrical refinement via density functional theory reveal a variety of matrix/peptide interactions. Most matrix-tripeptide clusters are bound through the side chains of the amino acids. In all clusters, the ionization potential (IP) of the matrix bound to the tripeptide is reduced relative to that of the free matrix. The origin of this IP lowering is discussed. In many cases, ionization of the cluster resulted in spontaneous proton transfer between the matrix and the tripeptide. The exothermicity of the spontaneous proton transfer reaction is considerably greater for the 2,5-DHB and HCCA clusters than for the 3,5-DHB clusters. This is of significance because the former two matrices are known to be very effective matrices for the MALDI process, while 3,5-DHB, although structurally similar to the others, is completely nonfunctional as a MALDI matrix.