Transcript at ICAM Workshop, Boston (2004)
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: Which features of a coarse-grained model for A are essential to predict the structure of A aggregates in silico? What is A-42 monomer structure? A-42 sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA green...hydrophobic white...glycines (9,25,29,33,37,38) A in media that mimic apolar microenvironments (Crescenzi et al. , 2002) purple...a-helical s.s. 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 A monomer a-helical 3-strand 4-strand T=0.108 T=0.115 T=0.100 a-> at T=0.107 ->RC at T=0.128 -hairpin -hairpin stable at 0.117<T<0.127 T=0.120 A model dimer conformations Planar -strand conformations Characteristics of these dimer conformations: (1) each peptide is in -hairpin conformation with 2 -strands; (2) all 4 -strands are planar. NN-para NN-anti NC-para NC-anti CC-para CC-anti 4 additional planar -strand dimers with “nested” conformations: para nest-para para nest-anti anti nest-para anti-nest-anti -turn in dimers well defined: between Asp-23 and Lys-28! Explanation: presence of glycines makes the turn well defined 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)]. RESULTS (i) the simple coarse-grained model predicts a monomer structural transition from a-helical to -strand conformations; (ii) model planar -strand dimers are characterized by a -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 -strand dimer conformations are energetically unfavorable compared to a-helical monomer conformations in water; (iv) free energy comparison between A-40 and A-42 dimers in water shows no significant difference between the two alloforms; A oligomerization is not accompanied by the formation of stable planar -strand A oligomers.