The mechanism for amyloid formation in a model peptide
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
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.
Technical Summary
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.
Publications
Strodel B
(2008)
Implicit Solvent Models and the Energy Landscape for Aggregation of the Amyloidogenic KFFE Peptide
in Journal of Chemical Theory and Computation
Strodel B
(2007)
Thermodynamics and kinetics of aggregation for the GNNQQNY peptide.
in Journal of the American Chemical Society
Strodel B
(2010)
Transmembrane structures for Alzheimer's Aß(1-42) oligomers.
in Journal of the American Chemical Society
Strodel B
(2008)
Free energy surfaces from an extended harmonic superposition approach and kinetics for alanine dipeptide
in Chemical Physics Letters
Strodel B
(2008)
Characterizing the first steps of amyloid formation for the ccbeta peptide.
in The journal of physical chemistry. B
Malolepsza E
(2012)
Erratum: Symmetrization of the AMBER and CHARMM force fields [J. Comp. Chem. 31, 1402]
in Journal of Computational Chemistry
Malolepsza E
(2010)
Symmetrization of the AMBER and CHARMM force fields.
in Journal of computational chemistry
Klenin K
(2011)
Modelling proteins: conformational sampling and reconstruction of folding kinetics.
in Biochimica et biophysica acta
Bauer MS
(2010)
Interpolation schemes for peptide rearrangements.
in The Journal of chemical physics
Description | ERC Advanced Grant |
Amount | £2,000,000 (GBP) |
Funding ID | ERC-AdG 267369 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2011 |
End | 03/2016 |
Description | Multiscale Modelling of Protein Aggregation |
Amount | £1,500,000 (GBP) |
Organisation | Julich Research Centre |
Sector | Academic/University |
Country | Germany |
Start | 02/2009 |
End | 01/2015 |
Description | Multiscale Modelling of Protein Aggregation |
Amount | £1,500,000 (GBP) |
Organisation | Julich Research Centre |
Sector | Academic/University |
Country | Germany |
Start | 01/2009 |
End | 01/2015 |
Description | Programme grant for self-organisation involving Cambridge, Oxford and Birmingham. |
Amount | £3,187,961 (GBP) |
Funding ID | EP/I001352/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2010 |
End | 01/2015 |
Title | OPTIM |
Description | Program for characterising pathways and mechanisms |
Type Of Material | Improvements to research infrastructure |
Provided To Others? | Yes |
Impact | wordwide use of group software |
URL | http://www-wales.ch.cam.ac.uk/OPTIM/ |
Title | PATHSAMPLE |
Description | Program for rare event dynamics and construction of kinetic transition networks |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | Acceleration of rare event dynamics simulations in many groups |
URL | http://www-wales.ch.cam.ac.uk/PATHSAMPLE/ |
Description | Evotec |
Organisation | Evotec |
Country | Germany |
Sector | Private |
PI Contribution | Structure prediction for drug binding |
Collaborator Contribution | Target systems provided |
Impact | Publications were accelerated |
Start Year | 2008 |
Title | GMIN |
Description | global optimisation |
Type Of Technology | Software |
Open Source License? | Yes |
Impact | widespread use if basin-hopping |
URL | http://www-wales.ch.cam.ac.uk/GMIN/ |
Title | OPTIM |
Description | characterisation of pathways and mechanisms |
Type Of Technology | Software |
Year Produced | 2006 |
Open Source License? | Yes |
Impact | widespread use of hybrid eigenvector-following |
URL | http://www-wales.ch.cam.ac.uk/OPTIM/ |
Description | ESF Energy Landscapes conference (Austria; JMC) |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | No |
Type Of Presentation | paper presentation |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation given by the PDRA funded on grant EP/H042660/1 to attendees at the Energy Landscapes ESF conference, Obergurgl, Austria, July 2012. The questions asked during/after the talk suggested that people were receptive to the novel approach presented. |
Year(s) Of Engagement Activity | 2012 |
Description | Energy landscapes workshop and conference (Durham) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Around 50 researchers attended a talk on optimisation methodology , which sparked questions and discussion afterwards. A number of attendees have expressed interest in using the described methodology in various contexts. |
Year(s) Of Engagement Activity | 2014 |
URL | https://www.dur.ac.uk/soft.matter/events/energylandscapes/programme/ |
Description | Inaugural ESF Energy Landscapes Meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | The ESF funded an inaugural Energy Landscapes meeting,in Obergurgl Austria, 2012, which featured several talks on amyloid, including one from the PDRA on the original BBSRC grant. Prof. Wales was Conference Chair and Organiser. 40,000 euros Prof. Wales was Conference Chair and Organiser. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2012 |
Description | Q and A session |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Hockerill Anglo-European College. Successful university applications |
Year(s) Of Engagement Activity | 2011 |