TY - JOUR
T1 - The conformational preference of Cα-centered radicals in proteins
AU - Owen, Michael C.
AU - Komáromi, István
AU - Murphy, Richard F.
AU - Lovas, Sándor
N1 - Funding Information:
This work was supported by NIH-BRIN grant 1 P20 RR16469 and the Carpenter Endowed Chair in Biochemistry, Creighton University.
PY - 2006/2/14
Y1 - 2006/2/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=32644469108&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=32644469108&partnerID=8YFLogxK
U2 - 10.1016/j.theochem.2005.10.047
DO - 10.1016/j.theochem.2005.10.047
M3 - Article
AN - SCOPUS:32644469108
VL - 759
SP - 117
EP - 124
JO - Computational and Theoretical Chemistry
JF - Computational and Theoretical Chemistry
SN - 2210-271X
IS - 1-3
ER -