Computational Methods for Fragmentation of Organic and Biomolecule Ions
The mass spectrometry (MS) research resource is pursuing theoretical approaches to the study of the fragmentation processes of various classes of biomolecules. Our goal is to provide theoretical understanding of mechanisms and structures to complement the experimental data on the fragmentation processes. We are approaching these problems by using density functional and ab initio calculations as implemented in Gaussian 98/03. We employ Spartan (Linux) for graphical setup, visualization, and survey calculations. To carry out this work, we have set up a small cluster of Dell workstations running Linux devoted to these calculations. To augment the empirical data, we also employ selective isotopic labeling of the precursor molecules in addition to comparison of products ions with those obtained from model compounds.
One focus is developing analytical methods for biomarkers. We have chosen the fragmentation of modified nucleobases, adducted by polycyclic aromatics hydrocarbons or modified steroids, as one example. Another focus grows from the long-term interest at this research resource in the structural determination of various classes of lipids. These systems are discussed to provide a “flavor” of our work and our capabilities.
Lipids: Theoretical calculations on the acid, ethanolamine (basic) and glycerol (neutral) classes of diacetylglycero-phosphatidic lipids provide an understanding of the relative mechanistic preferences of fragmentation based on headgroup acidity.
The mechanism of ketene loss, according to theoretical calculations, involves the transfer of an acyl group from the backbone to phosphate oxygen, a process that uncovers an alkoxide anion that can abstract an ?-H+ prior to loss of ketene.
Nucleobases modified with steroids: Survey of a potential-energy surface indicates that the generation of the prominent radical cation in the product-ion spectra of the even-electron precursor likely arises from H• transfer in an ion-dipole complex rather than direct loss of a radical.
Nucleobases modified with PAH: Empirical evidence indicates a general preferential formation of aryl cyanide vs aryl radical cations from the C-8 but not from the N-7 guanines that are adducted with benzopyrene and related adducts. Theoretical calculations indicate that the C-8 adducts generate true aryl cyanides, whereas the N-7 isomers generate instead the aryl isocyanides which are higher energy products.
Fragmentation of Small Gas-Phase Ions: Theory & Experiment
The focus this research is the fragmentation of biologically significant ions. We do this be adopting small ions exhibiting analogous reactions and exploring these models by ab initio and density functional methods. The calculations are executed to obtain thermochemical information, structures, and transition states for fragmentation processes, along with ion-molecule reactions of various small molecule ions and their subsequent patterns of fragmentation. The complementary empirical data is generated by experiments using MS/MS (ion trap, tandem sector, FTMS), kinetic-energy release, isotopic labeling, reactivity correlation, and other tools that are important in mechanistic studies. This is a unique area of research for Research Resources in the mass spectrometry area, and our goal is to be a resource for understanding important mass spectral fragmentation of biological molecules.
Systems of interest are possible cyclizations that occur with great difficulty in neutral molecules. There may be opportunities to accelerate these slow reactions involving Diels-Alder condensation by making one of the reagents a radical cation or a closed shell ion by protonation. The latter systems can be studied by ESI or FAB whereas the former reactions are possible cycloaddition reactions involving five-membered ring heterocycles (furan, thiophene, pyrrole). If ionization can accelerate reaction rates, new opportunities for chemical synthesis of drugs and related materials will arise.
Adducts formed from the radical cations of furan, thiophene and pyrrole reacting with acetylene in the gas phase all exhibit analogous dominant product ions upon MS/MS. Theoretical calculations show that the initial condensation of radical cations with acetylene proceed by cyclobutanation rather than the Diels-Alder reaction. The routes to the dominant fragments are analogous and pass through similar seven-membered rings (i.e. oxepin, thiapin, and azepine radical cations).
Joseph T. Moolayil, Mathai George, R. Srinivas, Daryl Giblin, Amber Russell, Michael L. Gross, Protonated Nitro Group as a Gas-Phase Electrophile: Experimental and Theoretical Study of the Cyclization of o-Nitrodiphenyl Ethers, Amines, and Sulfides, J. Am. Soc. Mass Spectrom., 18, 2204-2217 (2007).