The aggregation of the 42-residue form of the amyloid-β peptide
(Aβ42) is a pivotal event in Alzheimer’s disease (AD). To solve this question, we want to perform molecular dynamics approach to develop a rational drug discovery strategy against Aβ42 aggregation at molecular level. In fact, the kenetic aggregationof Aβ42 has been stuied recently, understanding the deggreagation design of Aβ42 is also important when small molecules (i.e., drug molecules) get into the activate site.
You may think about trying to search for some small molecules which can specifically interact with the native conformation(s) of single of Aβ42 peptide to slow down or completely alter the aggregation process from the beginning (e.g. just by making it more soluble). You also should consider the blood-brain barrier for your screening study.
There are several problems regarding the study by molecular dynamics (MD) of the effect of ligands on amyloid aggregation:
1. Choice of the amyloid aggregate. There are several structures in the PDB depository. Most of them are NMR structures of AB1-40, the most toxic species. For starters you should choose one of them for your studies.
2. Starting location and pose of your ligand. You could try 'docking' your ligand in some position, guided by software like GOLD, DOCK, etc. Then, you should take some of the results as the starting point for parallel MD simulations
3. The environment. You should try your simulations in water and lipid bi-layers. The latter environment favors the formation of non-helical structures that are found in aggregates.
You are advised to review the literature as some of the issues raised here have been already been dealt with previously.
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