Monte carlo simulations on mixed resolution protein models

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Monte carlo simulations on mixed resolution protein models Sundar Raman Subramanian Zuckerman Lab MMBioS meeting 5/29/2014

Quality of the Model vs Computational cost Modeling of HIV protease at various resolution to sample the flap region Dynamics of this flap influences the binding affinity of Ligand/Inhibitor to HIV protease Quality of the Model Computational Cost Fully Atomistic Mixed Resolution Fully coarse grained

HIV Protease- Flap Dynamics Starting structure Flap in closed conformation PDBID: 1HPX without Ligand Total amino acids per chain is 99 All atom Residues: chain A: 45 to 54 Chain B 45 to 54 Coarse Grained Residues chain A: 1 to 45 chain B: 55 to 90 90°

Mixed Resolution for Ligand Docking Structure of Estrogen Receptor alpha with Estrogen Coarse-grained region is shown in Pink All atom region is Estrogen and receptor amino acids within 6Ang. of Estrogen CG side chains has atomistic details and AA side chains interact with them atomistically (PDBID: 1ERE)

Recovery of Estrogen Binding Pose Collaborators: Prof. Andrew Stern & Prof. Steffi Oesterreich Labs

Ligand Spotlight: Ligand Decides the Resolution of Protein Residues Interaction of ligand with Cyclin-dependent kinase 2

Challenges and Future Directions Improvements on side chain interactions of coarse grained residues (better Go model?) Optimization of parameters Automated process for the preparation of ligand parameters Tests on various systems Heat shock proteins Mutants of Estrogen receptor Binding of ligands to Estrogen receptor and its mutants