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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.