The conformational preference of C^α-centered radicals in proteins

Free radical-induced aggregation of amyloid beta (Aβ) peptide is a recently proposed mechanism in which C^α-centered radicals can form on either Gly33 or Gly29 of Aβ(1-42). Limited structural data for the glycyl radical are available. In this study, the structure of N-Ac-Gly-NHMe and N-Ac-Gly^.-NHMe was determined using ab initio and DFT calculations. E=f(φ,ψ) potential energy surfaces (PES) were constructed by independently constraining the φ and ψ angles, 30°apart from 0 to 360°. The structure of each conformer was subsequently optimized using Hartree-Fock and DFT calculations, and the relative energy was calculated using B3LYP/6-31G(d,p). The Poisson-Boltzmann (PB) solver was used to simulate an aqueous environment. The PES of N-Ac-Gly-NHMe was flat, displaying the ability of Gly to sample conformations in both the L and D configurations. Conversely, the N-Ac-Gly^.-NHMe had a global minimum in the β_L conformation, with a high-energy barrier preventing transitions to other minima. The restricted β conformation of N-Ac-Gly^.-NHMe corresponds to the anti-parallel β-sheets observed in Aβ aggregates. The β conformation permits inter-strand H-bonding that could stabilize the aggregates.