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.