title: Construction of the Free Energy Landscape of Peptide Aggregation from Molecular Dynamics Simulations.
abstract: To 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.
authors.affiliation: Biomolecular Dynamics, Institute of Physics, Albert Ludwigs University , 79104 Freiburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Riccardi
authors.affiliation: Laboratoire de Biochimie Theorique - UPR 9080, Institut de Biologie Physico-Chimique , 13, rue Pierre et Marie Curie, F-75005 Paris, France.
authors.forename: Phuong H
authors.initials: PH
authors.lastname: Nguyen
authors.affiliation: Biomolecular Dynamics, Institute of Physics, Albert Ludwigs University , 79104 Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Stock