The document discusses determining the interface of alpha synuclein dimer, which is important for understanding protein aggregation in neurodegenerative diseases like Parkinson's. The researchers are using homology modeling and molecular docking simulations to develop potential structures of alpha synuclein monomers and dimers. They plan to run long coarse-grained simulations to better study the dynamics of the interface between two monomers and identify interacting residues. Understanding this interface could help design pharmacophores to disrupt dimerization and prevent oligomer formation implicated in Parkinson's disease.

1. Determining the interface of alpha synuclein dimer
Kamlesh K. Sahu1, Jack Tuszynski1,2
1 – Department of Physics, University of Alberta, Edmonton, AB, Canada
2 - Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
Homology Modeling Simulations and virtual screening protocol
α-Synuclein (SNCA-140
AA)
(downloaded seq from
uniprot-P37840)
Sequence similarity search
using blast
Homology models based
on PDBs 3Q26, 3Q27,
3Q28, 3Q29
COMPOUNDS SATISFYING PH4
LEAD-LIKE DATABASES
–Currently we have conformational
databases of leadlike on the shelf available
compounds from different vendors
Pharmacophore
search (MOE)
HIGH RANKING DOCKED
POSES
Docking
DOCKED POSES
SATISFYING PH4
Post filtering
DETERMINE THE INTERFACE OF DIMER AND
LOOK FOR STABLE INTERFACE
–Long Coarse Grained Simulations
DETERMINE THE STRUCTURE OF THE DIMER
– Docking + Monte Carlo simulation- clustering
We are currently working on
simulating alpha-synuclein
dimer for a very long time that
is possible with coarse grained
simulation. This simulation
will help determine the part of
alpha-synuclein that forms
interface in dimer.
On the
basis of
3Q28
On the
basis of
3Q29
On the
basis of
3Q27
On the
basis of
3Q26
Interactions of amino acids between two alpha-synuclein monomers may best be looked into by
MD simulations which may allow us to look into molecular level of details but phenomenon of
aggregation of this intrinsically disordered protein may occur over lengths and time scales that are
beyond the capabilities of all-atom MD. So we intend to run coarse grained simulation.
Aggregates of protein alpha-synuclein have been found in Parkinson’s disease and other neurodegenerative diseases. In order to prevent this aggregation, the interface of two monomers
should be studied and interacting residues should be identified. This work is an effort to identify the probable structure of monomer and then dimer so that the residues contributing to the
interaction can be identified and targeted. We wish to run long coarse-grained simulations to study the dynamics of interface between two monomers. This will help us in elucidating a
pharmacophore to disrupt this interaction using small molecule. This pharmacophore can be used to screen corporate databases for small molecule that can bind to the interface with greater
affinity as compared to the other monomer. If we succeed to prevent dimerization, we will prevent formation of synuclein oligomers that are hallmark of Parkinson’s disease.
Method
Molecular operating environment1 (MOE) was used to homology model the SNCA sequence
downloaded from Uniprot ID P37840. Basic Local Alignment Search Tool2 (BLAST) and other
sequence analysis tools was used to search for suitable template.
References -
1- Molecular Operating Environment (MOE), 2012.10; Chemical Computing Group
Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A
2R7, 2012.
2- Altschul, Stephen; Gish, Warren; Miller, Webb; Myers, Eugene; Lipman, David
(1990). "Basic local alignment search tool". Journal of Molecular Biology 215 (3):
403–410
Homology models will be used
to select the best starting
point(s) for coarse grained
simulations. We have monte
carlo simulation trajectories of
SNCA monomers and dimers.
We think if we continue
simulating mon- and dimers for
longer time (which is possible
using coarse grained
simulation, we can have better
idea of dimer configuration.