BBSRC DTP White Rose Studentship - A new mathematical framework for Aβ peptide assembly in Alz

Amyloids are fibrous assemblies of misfolded protein which are responsible for a wide range of neurodegenerative diseases. While traditional models of nucleated polymerisation have been successfully applied to amyloid assembly under simplified experimental conditions, specific conditions in the human brain result in heterogeneous populations of immature assembly intermediates which add considerable complexity to the amyloid formation pathway. Although both atomistic and coarse-grained molecular dynamics simulations have provided crucial insights into the formation of these assemblies and their maturation into amyloid fibrils, computational limitations have prevented modelling of the entire amyloid assembly pathway. Moreover, although biochemical studies have provided evidence for positive feedback, by which mature fibrils facilitate the nucleation of additional amyloid fibrils and lead to spread of disease in the brain, the precise mechanistic details of this process have not been uncovered.

As part of an exciting new collaboration between the departments of Molecular Biology & Biotechnology and Physics & Astronomy at Sheffield, we are incorporating experimental biophysical and biochemical data into a realistic coarse-grained computational model of the amyloid-β (Aβ) peptide, the causative agent in Alzheimer’s disease. For this project, the successful candidate will take advantage of Sheffield’s high-performance computing facilities, including dedicated state-of-the-art Tesla P100 GPUs, to carry out large-scale Langevin Dynamics and Monte Carlo simulations using coarse-grained models. These simulations, which will be validated by additional atomistic dynamics simulations and comparison with structural and biophysical data, will then be used to predict the topology of amyloid assembly networks, and their associated transition rates and free energy changes. The physical data generated will then be incorporated into a generalised mathematical model of pathogenic Aβ assembly.

This project spans the fields of theoretical biophysics and computational structural biology. Techniques used will include molecular modelling, analysis of protein structures, statistical physics, and mathematical/computational modelling of the chemical kinetics of amyloid assembly. Together, the collaborators are part of a team of biochemists, physicists, and physical chemists studying the mechanistic basis of amyloid assembly. Due to the interdisciplinary nature of this project, applicants from physics, biology, applied mathematics, chemistry, or computer science will be considered. Because this project is primarily computational, prior experience of programming is essential. Experience in biochemistry/biophysics, molecular modelling, and/or statistical physics is desirable.

Funding Notes

4 year BBSRC studentship, under the BBSRC White Rose Mechanistic Biology DTP
https://www.whiterose-mechanisticbiology-dtp.ac.uk/

We welcome applications from students with first degrees in Biological, Chemical or Physical Sciences. For successful applicants, the studentships would provide funding for tuition fees and living stipend at the current Research Council UK rates (subject to eligibility) for 4 years. Please note that EU citizens must have lived in the UK for at least 3 years to be eligible for full support.

Applicants should have or expect to achieve an undergraduate honours degree at 2.1 or higher in a relevant field

https://www.sheffield.ac.uk/mbb/postgraduate/phd/projects_fully_funded