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Simulating the first steps of amyloid peptides aggregation
Jessica Nasica
Département de physique - Université de Montréal
GEPROM – 2ième réunion scientifique
May 27th, 2009
Overview of the presentation Medical interest
Problem of amyloid fibril formation
Our simulations & results
Protein misfolding and aggregationMany protein-misfolding diseases include conditions where a protein
forms insoluble aggregates, amyloid fibrils, that deposit toxically Amyloid diseases
e.g. : - Alzheimer’s- Parkinson’s- Huntington- type II diabetes
Dobson et al. (2003), Nature 426
Amyloid fibril formationAmyloid fibrils insoluble fibrous aggregates with a highly organized Macrostructure made of β-sheets.
Mechanism of formation 3 steps:1. Alignment of the molecules to form β-sheets fastest stage
involves H-bonds
2. Formation of the cross-β structure slower than step 1 involves Van-der-Waals forces interdigitation of residues side chains “steric zipper” structure
3. Fibril formation involves non-covalent bonds
Amyloid fibril formation is a nucleated-growth process stabilized by the protein concentration and by the formation of steric zippers
Nelson et al. (2005), Nature 435
Amyloid fibril polymorphism
Petkova et al. (2006), Biochemistry 45Paravastu et al. (2008), PNAS 105 &
For the Aβ40 sequence, they construct a full molecular model showing 2 distinct possible morphologies for the fibril structure.
Amyloid oligomers
intermediate states during the formation of amyloid fibrils
thought to be more toxic than the fibrils themselves
Different types of soluble amyloid oligomers share a common structure suggests they share a common toxicity mechanism
Lashuel et al. (2002), Nature 418
Kayed et al. (2003), Science 300
Theories on intermediate oligomer states Oligomers as protofibrils
Oligomers as pores may form annular pore-like structures to go through the cell membranes : β-barrel
Irbäck et al. (2007), Proteins 71
Esposito et al. (2006), PNAS 103
Lashuel et al. (2008), Nature 418
Amyloid oligomer pore structure observed experimentally (left) & numerically (right)
The “short peptides” approach
The gain-of-interaction model for amyloid structure suggests that
only a small portion of a native protein is responsible for amyloid fibrils.
Under conformational changes
this small portion is exposed & binds to an identical portion on another molecule
builds up a fibril
or
Cross-β spine (no domain swapping) Cross-β spine with domain swapping
The essential element involved in the fibril structure is the small portion
Nelson et al. (2006), Current opinion in structural biology 16
GNNQQNY GNNQQNY
For the budding yeast Sup35p fibril-forming protein
Experiments done on GNNQQNY
Nelson et al. (2005), Nature 435
Atomic structure of cross-β spine constructed from X-ray diffraction analysis
Fomation of a double β-sheet with parallel β-stands
Side chains form a self-complementing steric zipper
Interdigitation of the side-chains would stabilize the sheets
Our short-term goals
To understand the aggregation process of short peptides Kinetics of aggregation Final structures (morphologies accessible)
To study different sizes of systems Trimer GNNQQNY Pentamer GNNQQNY 20-mer GNNQQNY 50-mer GNNQQNY
Our simulation methodsReplica exchange MD
1. launch n molecular dynamical simulations in parallel, at n different temperatures
2. at regular intervals, try an exchange of configurations between two adjacent temperatures using a Metropolis accept-reject criterion
REMD accelerates sampling (in some cases) for the cost of losing dynamical information.
REMD still provides thermodynamical information
Final structures of simulations tested with an all-atom potential (GROMACS)
Our simulations : small aggregates
GNNQQNY trimer
GNNQQNY pentamer
We observe a strong tendency to form planar β-sheets
Our simulations : bigger aggregates GNNQQNY 20-mer – 300 ns simulation
Formation of twisted pair-of-sheet “protofibril-like” structuresFormation of β-barrel-like structures
Similar to the atomic structure described by Nelson et al. (2005)
GNNQQNY 20-mer results
We observe a nucleated-growth aggregation process
a clear loss of entropy as the energy of the system drops rapidly
&
GNNQQNY 20-mer results β-sheets favor a parallel orientation of the β-strands Consistent with the atomic description given by Nelson et al. (2005)
Statistics over 300 ns
Conclusions
We have described the first steps of aggregation of GNNQQNY. The results are consistent with experimental results on that sequence.
Polymorphism exists and we already see a clear separation between 2 different semi-organized structures.
The obtained β-barrel-like structures might not be on the fibril formation pathway. It seems it is a separate possible morphology.
For small aggregates (trimers, pentamers), the study of 2 other sequences (SSTSAA,SNQNNF) shows similar features compatible with the GNNQQNY results.
Future work Lots of statistics obtained from our 20-mer
simulations a lot of the analysis is still being done to understand
The formation process The triggering of the nucleated-growth process
Simulation of the GNNQQNY 50-mer
Simulation on other short sequences (SSTSAA, SNQNNF,…)
Acknowledgments
Collaborators
MONTREAL- Normand Mousseau
PARIS- Philippe Derreumaux
MILAN- Giorgio Colombo- Massimiliano Meli (Ph.D.)
Funding
- GEPROM- CRSNG- FESP
Resources
- Réseau québécois de calcul de haute performance
Special thanks to:Rozita Laghaei (post-doc), Lilianne Dupuis (Ph.D.) and Jean-François St-Pierre (Ph.D.)