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The mechanism for amyloid formation in a model peptide

Reference	BB/D000718/1
Principal Investigator / Supervisor	Professor David John Wales
Co-Investigators / Co-Supervisors	Professor Sir Christopher Dobson, Dr Emanuele Paci, Professor Michele Vendruscolo
Institution	University of Cambridge
Department	Chemistry
Funding type	Research
Value (£)	223,317
Status	Completed
Type	Research Grant
Start date	01/01/2006
End date	31/12/2008
Duration	36 months

Abstract

This project aims to discover the detailed mechanism for the conformational changes leading to the characteristic cross-beta structure observed in amyloid formation. It falls within the cross-committee priority areas of theoretical biology and biophysics, and is also relevant to important aspects of the biology of the transmissible spongiform encephalopathies. Using the newly developed discrete path sampling (DPS) approach it is now possible to elucidate mechanisms and calculate rates for processes that were previously beyond the reach of computer simulation. The ccbeta peptide recently characterised by Prof. Dobson and coworkers is an ideal system for the present study. It is small enough for the simulations to be feasible, yet large enough to embody most of the generic features of amyloid formation. Mutants have already been studied experimentally, and the native and cross-beta conformations have been characterised in considerable detail. This structural information will be used to construct the end-points required to begin a DPS simulation. Suitable ensembles of states will be obtained from molecular dynamics simulations. The DPS algorithm will then sample pathways between these states to calculate rates in a systematic fashion, without any further information concerning the reaction coordinate. Pathways and rates will also be calculated for the mutants that have already been studied experimentally. The Met mutant exhibits faster aggregation, while the chemically modifed form with a more hydrophobic residue does not appear to form fibrils on the experimental time scale. A detailed understanding of these differences in terms of specific mechanistic details would therefore provide considerable new insight into the aggregation process. Predictions will then be made for systematic non-disruptive mutations of other side chains. A detailed analysis of the corresponding pathways will be used to identify features that may be probed in future experiments to be carried out in the group of Prof. Dobson. These results should have general significance, given the many common features of amyloid formation by different proteins, including those implicated in disease.

Summary

Proteins are chains constructed from twenty different amino acids, which must fold up into a biologically active form after they are synthesised in cells. The functional proteins play essential structural and catalytic roles in all living organisms. However, when proteins misfold they can form well-defined aggregates, generically known as amyloid, and it is now known that a wide variety of proteins can be induced to form amyloid under appropriate conditions. Amyloid formation has been implicated in a number of serious diseases, such as Alzheimer's (senile dementia), bovine spongiform encephalopathy (mad cow disease), and Creutzfeld-Jacob disease (the human form of mad cow disease). It is also associated with diabetic conditions caused by poorly chosen diets, as well as inherited traits, such as early onset forms of dementia. The realisation that aggregation can occur for a wide range of proteins under suitable conditions is relatively recent, and many fundamental questions concerning amyloid formation are still unresolved. Although there is general agreement that aggregation is induced by a conformational change from the native structure to a generic sheet-like structure (related to that in silk), little is known about the mechanistic details of this process, and discovering how it occurs is a key priority for the development of treatment for amyloid diseases. The conformational change appears to be self-propagating, since the rate increases as the reaction progresses. The goal of this project is to elucidate the mechanism by which the structure changes from a compact state into amyloid for a recently designed artificial protein. We aim to resolve this mechanism at an atomic level of detail using newly developed theory and computer simulation techniques. The results will provide important new insights into amyloid formation. In particular, more specific and precise methods to prevent and perhaps reverse amyloid formation may emerge, with important implications for the treatment of human disease, including aspects of ageing and conditions related to obesity and poorly chosen diets.

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	Ageing, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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