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Molecular Dynamics Simulations of Amyloid  Dimer Formation

Molecular Dynamics Simulations of Amyloid  Dimer Formation. Brigita Urbanc Center for Polymer Studies Boston University. Collaborators: L. Cruz, F. Ding, S.V. Buldyrev, H.E. Stanley (BU) D. Sammond, S. Khare, N.V. Dokholyan (UNC). Question:.

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Molecular Dynamics Simulations of Amyloid  Dimer Formation

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  1. Molecular Dynamics Simulations of Amyloid  Dimer Formation Brigita Urbanc Center for Polymer Studies Boston University Collaborators: L. Cruz, F. Ding, S.V. Buldyrev, H.E. Stanley (BU) D. Sammond, S. Khare, N.V. Dokholyan (UNC)

  2. Question: Which features of a coarse-grained model for A are essential to predict the structure of Ab aggregates in silico? What is Ab-42 monomer structure? Ab-42 sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA green...hydrophobic white...glycines (9,25,29,33,37,38) Abin media that mimic apolar microenvironments (Crescenzi et al. , 2002) purple...a-helical s.s.

  3. The coarse-grained model: 4-bead model with hydrogen bond interactions Polyalanine chain with 6 glycines (represented by 3 backbone beads) Structural transitions in a model Ab monomer a-helical 3b-strand 4b-strand b-hairpin T=0.100 T=0.108 T=0.115 T=0.120 a->b at T=0.107 b->RC at T=0.128 b-hairpin stable at 0.117<T<0.127

  4. Ab model dimer conformations Planar b-strand conformations Characteristics of these dimer conformations: (1) each peptide is in b-hairpin conformation with 2 b-strands; (2) all 4 b-strands are planar. CC-anti CC-para NC-para NC-anti NN-para NN-anti

  5. 4 additional planar b-strand dimers with “nested” conformations: para nest-para para nest-anti anti nest-para anti-nest-anti

  6. b-turn in dimers well defined: between Asp-23 and Lys-28! Explanation: presence of glycines makes the turn well defined

  7. Free energy calculations using continuous MD in explicit water (i) transformation from 4-bead to all atom representation [using all-atom template amino acids, optimization by Monte Carlo algorithm]; (ii) calculation of conformational free energy in water [Sigma MD program (Hermans et al., 1994), CEDAR force fields (Ferro et al., 1980; Hermans et al., 1984)].

  8. RESULTS (i) the simple coarse-grained model predicts a monomer structural transition from a-helical to b-strand conformations; (ii) model planar b-strand dimers are characterized by a b-turn between Asp-23 and Lys-28 in aggrement with Petkova et al., 2000; (iii) all-atom free energy study shows that all ten planar b-strand dimer conformations are energetically unfavorable compared to a-helical monomer conformations in water; (iv) free energy comparison between Ab-40 and Ab-42 dimers in water shows no significant difference between the two alloforms; Ab oligomerization is not accompanied by the formation of stable planar b-strand Ab oligomers.

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