The conformational preference of Cα-centered radicals in proteins

Free radical-induced aggregation of amyloid beta (Aβ) peptide is a recently proposed mechanism in which Cα-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 βL 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.