Many neurodegenerative diseases, including Alzheimer's Disease, are caused by the aggregation of peptides and proteins into amyloid fibrils. This is illustrated between 2:13 and 2:30 in [1]. Peptides and proteins are biological polymers that are made from 20 different kinds of building blocks (amino acid residues) that are linked together in a chain.
In Alzheimer's Disease fibrils are formed from a peptide called amyloid-beta (Aβ), which contains 40-42 amino acid residues. Copies of Aβ peptides can stack together as shown in Figure 1. Knowing the structures of fibrils associated with disease, and understanding how they form, can lead to new strategies for therapeutic treatments. The structure shown in Figure 1C is from an Alzheimer's disease brain, while Figures 1A and 1B show two different ways in which the same peptide has been found to stack in vitro. The fibrils in 1B and 1C consist of three protofibrils (shown in different colours), while the fibril in 1A consists of two protofilaments. In previous computational studies, molecular dynamics simulations have been used to investigate the stabiliy of protofibrils (e.g. [2]).
Figure 1: Molecular structures of three Aβ fibril polymorphs (from [3])
A recent paper suggest that, while being associated with Alzheimer's Disease, Aβ can protect against microbial infection [4].
In addition to the conformations shown in Figure 1, other conformations of this peptide have also been observed. This raises the question: does a protofibril retain its conformation, or can it "flex" from one conformation to another?
The aims of this project are to devise and implement computational methods to investigate whether an Aβ protofibral can "flex" from one conformation to another. Such a conformational change would require altering several torsion angles (i.e. rotating around chemical bonds) in a coordinated way, while ensuring that the structure does not clash severely with itself while changing shape.
[1] AlzheimerUniversal. (2010, July 29) Inside the Brain: Unraveling the Mystery of Alzheimer's Disease, [Video file]. Retrieved from https://www.youtube.com/watch?v=NjgBnx1jVIU
[2] Lemkul, J.A. and Bevan, D.R. (2010) Assessing the Stability of Alzheimer's Amyloid Protofibrils Using Molecular Dynamics The Journal of Physical Chemistry , 114, 1652-1660 doi: 10.1021/jp911079
[3] Tycko, R. (2015). Amyloid Polymorphism: Structural Basis and Neurobiological Relevance. Neuron, 86, 632-645, doi: 10.1016/j.neuron.2015.03.017
[4] Kumar, D.K.V., Choi, S.H., Washicosky, K.J., Eimer, W.A., Tucker, S., Ghofrani, J., Lefkowitz, A., McColl, G., Goldstein, L.E., Tanzi, R.E. and Moir, R.D. (2016) Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Science translational medicine, 8, 340ra72, doi: 10.1126/scitranslmed.aaf1059
The course "Computational methods in bioinformatics" (Chalmers: TDA507, GU: DIT741) is recommended, but not required.