¶¡ÏãÔ°AV

*To request access to the videoconference, email dsivak@sfu.ca

Synopsis

The molecular machinery of life is largely generated through the assembly of proteins into functional complexes. A particularly common form of protein self-assembly is that leading to filaments. These structures are widely used in nature, for instance as the basis of the cytoskeleton and the extracellular matrix. Protein filaments also a common form of pathological protein aggregation, involved in numerous diseases. Here I will present our minimal coarse-grained models [1] for dynamic self-assembly of two important classes of protein filaments – collagen fibrils, which are a crucial component of the extracellular matrix, and amyloid fibrils that are implicated in neurodegenerative diseases.

I will first discuss molecular design principles that yield robust characteristic structures of collagen-like fibrils and networks [2]. I will then turn to pathological amyloid aggregation and will discuss the mechanisms of amyloid formation and self-replication via disordered toxic aggregates [3-7]. I will show how our minimal coarse-grained model can provide quantitative comparison to experimental kinetic data of Alzheimer’s Aβ42 peptide aggregation and can guide the design of new experiments. The mechanistic insight from our simulations can help efforts to control protein assembly in diseases and aging, and can aid the design of artificial protein assemblies of desired structures.

[1] A. Hafner et al., Curr Op Struct Biol 58, 43 (2019).  [2] A. Hafner et al.,  Biophys J 119,  1791 (2020). [3] A. Å arić et al., PNAS 111, 17869 (2014). [4] A. Å arić et al., J Chem Phys, 145, 211926 (2016). [5] A. Å arić et al., Nat Phys 12, 874 (2016). [6] T. C. T. Michaels et al., Nat Chem 12, 445 (2020) [7] J. Krausser et al., PNAS 117, 33090 (2020).