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 <i>n</i> molecules, the method consists of three steps: (i) characterization of the <i>intramolecular</i> 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 <i>intermolecular</i> structure through the identification of all occurring aggregate states of the peptides (dimers, trimers, etc.); and (iii) construction of the <i>overall</i> conformational states of the system in terms of a product basis of the <i>n</i> “single-molecule” states and the aggregate states. Considering the Alzheimer β-amyloid peptide fragment Aβ<sub>16–22</sub> as a first application, about 700 overall conformational states of the trimer (Aβ<sub>16–22</sub>)<sub>3</sub> 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.