Rational Design of novel Matrices for MALDI MS assays: an in silico perspective

Matrices used in MALDI analytical-techniques are of paramount importance for the ionization process and efficient mass-charge spectral generation. Here, we explore the rational design of MALDI matrices from a computational-chemistry viewpoint, using algorithms based on quantum and statistical mechanics principles to calculate and analyze relevant physical-chemical properties of MALDI matrices. A total of 34 novel MALDI matrices based on Fluorene (SFS-, CN-SFS-, FL-), Dibromofluorene (FL-), Carbazole and Triphenylamine cores were analyzed, including DCTB and α-CNPVs as reference/control systems. Relevant physical-chemical parameters were calculated using ab initio, semiempirical and DFT methods with specialized quantum-chemistry software, employing High-Performance Computing (HPC) tools. The presence of -CN and -NO2 substituent groups increase the ionization-energy (Ei) in all matrices, which is suitable for the matrix-analyte Electron-Transfer process. Comparing SFS- with CN-SFS and FLA- matrices, the -CN group in the backbone breaks the molecular planarity and increase the Ei in 0.7 eV (67.54 kJ/mol), except when the -CN is combined with the -OCH3 group as substituent (Ei increases 0.6 eV). Comparing all matrices evaluated, the FLs have the major IP values (above 8 eV) alongside FLAs. On the other hand, the -OH group decreases the IP values, due to their positive mesomeric-effect. The next step is to evaluate other physical-chemical parameters such as UV-vis absorption in solid state, the solubility values on several solvents used in MALDI, and crystal formation. Finally, we emphasize that these results will allow the analysis of the physical-chemical behavior between compound families to detect useful patterns.