Molecular dynamics study of aggregation of amyloidogenic peptides in explicit water

Abstract

AbstractThe presence of amyloid fibrils is associated with a number of degenerative and serious human diseases. Nonetheless, the process of fibrillogenesis is still poorly understood. In this study, we present the results of a molecular dynamics investigation into the self‐aggregation of the amyloidogenic peptide FLVHSS, a six‐residue peptide belonging to the sequence of human islet amyloid polypeptide (hIAPP), capable of self‐association to form amyloid‐like fibrils. The simulations were performed at T = 300 K, using multiple replicas of FLVHSS monomer with random initial spatial distribution and orientation, in explicit water, set in a confined space volume (simulation box). Different simulations were carried out by varying initial atomic coordinates or initial atomic velocities and simulation box size. The formation of a unique aggregate (cluster) was observed within few nanoseconds from the beginning of all simulations. Structural analysis of the clusters clearly showed an elongated scalene ellipsoidal shape and a preferential parallel alignment of the peptides, roughly perpendicular to the main axis of the cluster and in extended conformation. The spatial arrangement of peptides in the simulated clusters appears to be similar to the spatial disposition of molecules in amyloid fibrils. An elongated scalene ellipsoidal shape was observed also in the final aggregate of the cluster growth simulation we also reported herein, indicating a tendency of cluster to grow along its major geometrical axis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem 112:1844–1851, 2012