Construction of the Free Energy Landscape of Peptide Aggregation from Molecular Dynamics Simulations

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., beta-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 beta-amyloid peptide fragment A beta(16-22) as a first application, about 700 overall conformational states of the trimer (A beta(16-22))(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.