Multiscale modeling of protofilament structures: A case study on insulin amyloid aggregates

Under certain conditions, proteins may undergo misfolding and form long insoluble aggregates called amyloid fibrils. The presence of these aggregates is often associated with various diseases. The molecular mechanisms governing the aggregation process are yet to be fully understood. The self-assembly of amyloid protofilaments occurs over extended time frames, making the simulation of such events problematic. In this work, we describe a pipeline for multiscale modeling protofilament structures. In the first stage, the self-assembly of short fibrillar oligomers occurs during coarse-grained docking simulations of multiple copies of aggregating peptides. Subsequently, symmetry criteria are used to select the highest-ranked oligomer structures. Selected models are then reconstructed to an all-atom representation and used for the assembly of longer protofilaments. Models are optimized using molecular dynamics. Final structures are selected using various scoring protocols. We evaluated this modeling procedure through the test prediction of insulin amyloid protofilaments whose experimental structures have been published recently. The resulting insulin protofilament models closely resemble the experimental structures. This work provides a proof of concept for the proposed modeling procedure aiming to predict amyloid protofilament structures that exhibit in-register and parallel arrangement of β-sheets based solely on the amino acid sequence of aggregating peptides.