Role of computer simulations in quantitative modeling of the fragmentation mechanisms and the energy thresholds in mass spectrometry

Computer simulations are used to interpret and guide experimental mass spectrometry (MS) results. Gas phase MS is a widely used tool to elucidate molecular structures, in particular for biological systems, and, thus, it is important to correctly predict the fragments in a MS experiment. Direct dynamics simulations, which can virtually replicate MS experimental conditions, are performed to study a zinc containing oligopeptide and organic ions, which are used in internal energy calibrations during electrospray ionization (ESI) in MS. In these atomistic simulations, two kinds of activation methods are employed: (i) collision induced dissociation, which involves collision of the ion with an inert gas, and (ii) thermal excitation, which excites vibrational modes of the ion at a given temperature. Following excitation with either method, the ion may undergo fragmentation, which also provides the bond dissociation mechanisms. The fragmentation can occur via a statistical or non-statistical process, depending on the excitation method and the way the ion dissociates. If statistical, these dynamics are described by Rice-Ramsperger-Kassel-Marcus (RRKM) theory, which gives the rate constants for these unimolecular reactions. The rate constants are used to evaluate Arrhenius parameters including the activation energy. The fragmentation mechanisms and energy barriers obtained from simulations are compared with the MS experimental results. The computational study of a model oligopeptide, which can be used as a zinc transporter in human bodies, reveals atomistic fragmentation pathways and bond dissociation energies. The first of its kind study, which involves a tetra-coordinated transition metal complex, produced mixed results in comparison to experiment, as only some fragments observed in simulations were common with the experiment. The simulations showed double or triple bond dissociations in the backbone to produce mostly a- and x-type ions, whereas, the experiment predicted single bond dissociation along the backbone and two dissociations in the Zn(II) binding sites giving b- and y-type ions. Since, the sidechains were not available to undergo direct collision with the inert gas, due to the tetra-coordinated nature of the zinc complex, the collision energy threshold was substantially higher than the activation barrier of thermal simulations. To further highlight the efficacy of direct dynamics simulations, the energy thresholds and fragmentation mechanisms of thermometer ions, used in the calibration of ESI, are also determined. Given the smaller size of the system, higher level of theory is used to perform computer simulations. The results of the simulations, with methyl-benzylpyridine and methyl,methyl-benzhydrylpyridine ions, corroborate the experimental energy thresholds and dissociation mechanisms. Especially, for methyl-benzylpyridine, there are two conflicting mechanisms for C-N bond dissociation suggested in the literature: one involves a direct bond cleavage (DC) and the other goes through a rearrangement process (RP). Simulations reported here only showed DC, supporting the more recent experimental findings.