Ground Electronic State of Peptide Cation Radicals: A Delocalized Unpaired Electron?

Abstract

Electron capture and electron transfer dissociations are bioanalytical methods for fragmenting cations after reduction by an electron. Previous computational studies based on conventional DFT schemes have concluded that the first step of these processes, the attachment of the electron, leads to extensive delocalization of the spin density in the intermediate radical cation. Here we show that most DFT methods produce unphysical results when studying single electron reduction of a dicationic peptide. This is not the case for post-HF methods and long-range corrected functionals that show satisfying electron affinities, intermolecular interaction energies, and spin density trends. Our results suggest that the charged group with the highest electron affinity on the precursor cation is also the site of spin density in the electronic ground state after electron attachment. These findings have important implications for the interpretation of experimental data from electron-based processes in biomolecules and may guide the development of new functionals.SECTION: Molecular Structure, Quantum Chemistry, General Theory E lectron capture dissociation (ECD) 1,2 and electron transfer dissociation (ETD) 3 are efficient fragmentation techniques, available on Fourier transform ion cyclotron resonance and ion trap or Q-TOF mass spectrometers, respectively. These methods have an important potential for the structural analysis of peptides or proteins. 4À6 Electron capture by, or transfer to, cationic peptides or proteins in the gas phase characteristically results in cleavage of NÀC R bonds, which makes these techniques complementary to collision-induced dissociation (CID) where peptidic bonds are cleaved. ECD and ETD also have some advantages compared with CID: they preserve labile post-translational modifications, and they allow fragmentation of larger peptides and even entire proteins without prior digestion, making these approaches particularly suitable for top-down proteomics.In ECD and ETD, a multiply charged cation is partially reduced by receiving one electron, thereby converting it from a closed-shell specie to an intermediate cation-radical that undergoes fragmentation. The exact mechanism(s) implicated in such a process are still a matter of active discussion from both computational and experimental points of view. 7À12 Although there is consensus that the spin must become localized on a backbone carbonyl carbon to precipitate cleavage of an adjacent NÀC R bond, the pathway the electron takes to reach the carbonyl remains unresolved. Does the electron attach itself directly to an amide π* orbital, which may be an excited state (the UtahÀWashington mechanism), 13,14 or are preliminary structural rearrangement(s) needed (the Cornell mechanism)? 1 Recent theoretical studies indicate that the vertical reduction of protonated peptides lead to a highly delocalized spin density in the ground state. Delocalization could extend to spatially remote charged groups (ammonium, 15,16 guanidinium, 17 histidinium, 18 amide and/or carbonyl...

Noncovalent Interactions in Density Functional Theory

“…For cases in which the underlying DFT method erroneously predicts the energy level of the highest occupied molecular orbital (HOMO) of an electron donor to be too close to the energy level of the lowest unoccupied molecular orbital (LUMO) of an electron acceptor, there will be too much charge transfer and this will result in significant overbinding. This problem stems from the "fractional charge" or "self-interaction" 13,87,[245][246][247] and can occur in molecule-radical complexes 41,248 in addition to molecule-molecule complexes. At this point in time, it appears that DCPs cannot easily correct for self-interaction errors in functionals in which this shortcoming is present.…”

The Early Life of a Peptide Cation-Radical. Ground and Excited-State Trajectories of Electron-Based Peptide Dissociations During the First 330 Femtoseconds

“…Again, the electronic states gave very similar excitation energies for all three density functionals, and consisted of the closely spaced ground state (X) and excited states A, ΔE=0.07-0.09 eV, B, ΔE=0.16-0.19 eV and C, ΔE=0.52-0.62 eV (Figure 3). The DFT methods differed in wave function nodality for these electronic states and also in the extent of electron delocalization in the X state which was greatest for B3LYP and lowest for M06-2X (Figure 3) [58]. However, the wave functions from CAM-B3LYP and M06-2X calculations were substantially delocalized in the excited states, as illustrated by the A state from cam-B3LYP and the B state from M06-2X (Figure 3).…”

Dispersion-correcting potentials can significantly improve the bond dissociation enthalpies and noncovalent binding energies predicted by density-functional theory

“…31 This was demonstrated recently for the tetrathiafulvalene−tetracyanoquinodimethane dimer 32 and for molecule-radical complexes. 33,34 However, this problem (and similar issues related to the ab initio prediction of electronic spectra, see for example, Refs. 35 and 36) can be alleviated by employing range-separated functionals, 37 wherein the Coulomb operator is split into short-range and long-range contributions using the standard error function.…”