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* Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts; and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina
Correspondence: Address reprint requests to B. Urbanc, Center for Polymer Studies, Dept. of Physics, Boston University, Boston, MA 02215. E-mail: brigita{at}bu.edu.
Recent experiments with amyloid ß (Aß) peptide indicate that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Aß oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Aß dimer formation. 1), We use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations; and 2), we employ all-atom molecular mechanics simulations to estimate thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Aß peptide model predicts 10 different planar ß-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Aß(1–42) and Aß(1–40) dimers. We find that 1), dimer conformations have higher free energies compared to their corresponding monomeric states; and 2), the free-energy difference between the Aß(1–42) and the corresponding Aß(1–40) dimer conformation is not significant. Our results suggest that Aß oligomerization is not accompanied by the formation of thermodynamically stable planar ß-strand dimers.
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