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Use of Molecular Dynamics Simulations to explore the
regulation of Liver Receptor Hormone in the presence
of small molecules
by Bernard Scott under supervision of Dr. Ivaylo Ivanov
Background
• LRH-1 is an orphan nuclear receptor for which the structure is similar
to many other known receptors but whose endogenous ligand is
unknown.
• LRH1-1 controls cell differentiation in the pancreas while also
maintaining cholesterol homeostasis and bile acid synthesis
• Is typically a downstream target of co-regulating proteins (such as
PDX-1)
• Its dysregulation is linked to breast cancer
• Its activity is modulated by bound phospholipids and co-regulating
peptides.
LRH-1/Tif-2 Active Site bound to ent-2
T352
Ent-2
Promising Results from Drug Discovery Effort
• The top 100 or so
compounds derived from
virtual screening of the
crystal structure pose
score better than Ent-2.
• Compounds ranking 100
had a docking score of 10.0kcal/mol.
Where to from here?
• Ligand based virtual screening on more polar compounds (derived from
structural architecture of phospholipids)
• Screening based on Molecular Dynamics Simulation of Ent-2/Tif-2 bound to
LRH-1 and other small molecules (on Comet using MPI and Cuda).
• Want to know how these small molecules regulate the protein
• Will use select compounds to do dynamics studies in hopes of elucidating
(agonistic, antagonistic, is the previously discovered mode of allostery
replicated or at least similar with new ligands) the dynamic motions that
govern regulation in presence of small molecules
• Post-processing of the simulation will PCA analysis (what “motions” are
correlated) and Dynamical Network Studies .
HPC Usage
• Will use XSEDE resources (Comet and Stampede) primarily.
• For a small portion of the molecular dynamics simulations (called
equilibration), MPI version of Amber (MD package) is used.
• The majority of the simulation (called the Production) often uses a
CUDA.MPI version of Amber
• Key tasks to optimize scaling involve optimizing the number of “steps”
per job and ensuring that my the version of Amber used matches the
organization of the jobs.
• Must be much more careful when assigning jobs as well.