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Computer simulation of metal-amyloid interaction and its role in plaque formation

Cardiff School of Chemistry

About the Project

Alzheimer’s disease is one of the greatest healthcare challenges facing 21st century society. AD is associated with formation of fibrils and plaques in brain tissue that impair proper functioning of neurons. Plaques are formed by aggregation of amyloid-beta peptides that are soluble in isolation, but insoluble when bound to one another. The presence of metals, notably copper, zinc and iron, is a vital part of the aggregation and subsequent toxicity of amyloid beta peptides: increased levels of Cu and Zn are found in plaque regions of diseased brain, and those plaques which do not contain metal ions have been found to be non-toxic. Moreover, different metals such as platinum and ruthenium have been shown to inhibit aggregation, opening new avenues for treatment and diagnosis.

Experiments to determine how metals might bind to amyloid beta peptides are difficult and costly to perform. In this light, using computers to simulate how metals bind to amyloid beta peptides and affect their structure and aggregation is an attractive proposition. This project will use modern simulation methods to describe in detail how metals bind to the peptides that cause AD, and the effect different metals have on their structure and aggregation characteristics. A suitable protocol for theoretical description of this important event must be able to properly describe the bonding and d-orbital effects that determine transition metal chemistry, while retaining the computational efficiency required for dynamical simulation of entire biomolecular systems. We have identified ligand field molecular mechanics (LFMM) as the ideal candidate for this task, as it efficiently and transferably captures the behaviour of metals. This project will use LFMM within molecular dynamics simulations to explicitly allow the peptide to change its shape in response to different metals. Crucially, the speed of LFMM coupled with the supercomputing resources available to us means that we can simulate the behaviour of two or more peptides together, and hence to examine the effect of metal on the initial stages of aggregation.

Supervisor: Dr James Platts

Academic criteria: We require applicants to have a 2.2 BSc or equivalent to be considered for PhD study.

If English is not your first language that you must fulfil our English Language criteria before the start of your studies. Details of accepted English Language qualifications for admissions can be found here


To apply please complete the online application - and state the project title and supervisor name

Funding Notes

This PhD post is open to self funded Home, EU and International students.

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