ct200911w_si_001.pdf (317.64 kB)
Construction of the Free Energy Landscape of Peptide Aggregation from Molecular Dynamics Simulations
journal contribution
posted on 2012-04-10, 00:00 authored by Laura Riccardi, Phuong
H. Nguyen, Gerhard StockTo describe the structure and dynamics of oligomers during
peptide
aggregation, a method is proposed that considers both the intramolecular
and intermolecular structures of the multimolecule system and correctly
accounts for its degeneracy. The approach is based on the “by-parts”
strategy, which partitions a complex molecular system into parts,
determines the metastable conformational states of each part, and
describes the overall conformational state of the system in terms
of a product basis of the states of the parts. Starting from a molecular
dynamics simulation of n molecules, the method consists
of three steps: (i) characterization of the intramolecular structure, that is, of the conformational states of a single molecule
in the presence of the other molecules (e.g., β-strand or random
coil); (ii) characterization of the intermolecular structure through the identification of all occurring aggregate
states of the peptides (dimers, trimers, etc.); and (iii) construction
of the overall conformational states of the system
in terms of a product basis of the n “single-molecule”
states and the aggregate states. Considering the Alzheimer β-amyloid
peptide fragment Aβ16–22 as a first application,
about 700 overall conformational states of the trimer (Aβ16–22)3 were constructed from all-atom molecular
dynamics simulation in explicit water. Based on these states, a transition
network reflecting the free energy landscape of the aggregation process
can be constructed that facilitates the identification of the aggregation
pathways.