An open-shell extension of the pair interaction energy decomposition analysis (PIEDA) within the framework of the fragment molecular orbital (FMO) method is developed. The open-shell PIEDA method allows the analysis of inter- and intramolecular interactions in terms of electrostatic, exchange-repulsion, charge-transfer, dispersion, and optional polarization energies for molecular systems with a radical or high-spin fragment. Taking into account the low computational cost and scalability of the FMO and PIEDA methods, the new scheme provides a means to characterize the stabilization of radical and open-shell sites in biologically relevant species. The open-shell PIEDA is applied to the characterization of intramolecular interactions in capped trialanine upon hydrogen abstraction (HA) at various sites on the peptide. Hydrogen abstraction reaction is the first step in the oxidative pathway initiated by reactive oxygen or nitrogen species, associated with oxidative stress. It is found that HA results in significant geometrical reorganization of the trialanine peptide. Depending on the HA site, terminal interactions in the radical fold conformers may become weaker or stronger compared to the parent molecule, and often change the character of the non-covalent bonding from amide stacking to hydrogen bonding.

Post-translational mechanisms of protein oxidation as a result of reactive oxygen species (ROS) can occur under physiological conditions to yield selective side-chain and backbone modifications including abstractions, donations, additions, substitutions, and fragmentation. In order to characterize the selectivity of radical-mediated fragmentation, quantum mechanical investigations using ab initio and density functional methods were employed to evaluate site, conformation, and pathway trends of small trialanine peptides resembling a β-strand and a β-turn. Comparisons of reaction enthalpies show that the diamide pathway is more energetically favorable than the α-amidation pathway and that both pathways are site and conformationally selective. These findings readily contribute to the understanding of oxidative stress in biochemical processes.

The work in this article describes a spectral signature for the detection of a C(α) radical damaged peptide, which should enable the use of infrared spectroscopic methods to directly monitor oxidative events. Spectra for radical damaged peptides are computed with ab initio methods. The amide bands A, I, II, and III are analyzed for trends in the damage site. The spectral signature is found in a region (i.e., 1700-1620 cm(-1)) normally void of vibrational absorption bands from stable undamaged beta peptides. An analysis of the vibrational motions of the spectral signature is described. The uniqueness of the spectral signature is explored by an examination and comparison with C(α) monoradicals and polyradicals, as well as with other bioradicals that could act as spectral interferences. The identification of unique infrared spectral features for C(α) damage could have important implications in diagnostics for beta conformational peptides damaged by oxidative stress processes.

a b s t r a c tTo quantify the thermodynamics for hydrogen abstraction lipids, the fragment molecular orbital method (FMO) is used to calculate structures and energies of the reactants and products. The analytic second derivative is developed for the open-shell Hartree-Fock formulation of FMO and used to calculate zero point energy corrections. The accuracy of FMO is evaluated for a lipid model and the errors in reaction energies are found not to exceed 0.5 kcal/mol. The reaction energies determined for multiple sites in two lipids are used to discuss likely sites and pathways of radical initiation in membranes.

Oxidative stress plays a role in many biological phenomena, but involved mechanisms and individual reactions are not well understood. Correlated electronic structure calculations with the MP2, MP4, and CCSD(T) methods detail thermodynamic and kinetic information for the free radical oxygen protein oxidation pathway studied in a trialanine model system. The pathway includes aerobic, anaerobic and termination reactions. The course of the oxidation process depends on local conditions and availability of specific reactive oxygen species (ROS). A chemical mechanism is proposed for how oxidative stress promotes β-structure formation in the amyloid diseases. The work can be used to aid experimentalists as they explore individual reactions and mechanisms involving oxygen free radicals and oxidative stress in β-structured proteins.