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Monte carlo simulations on mixed resolution protein models

Exploring the computational cost and quality of mixed resolution protein models through Monte Carlo simulations. Focus on modeling HIV protease flap dynamics and its impact on ligand binding affinity. Also, recovery of estrogen binding pose and challenges for future improvements.

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Monte carlo simulations on mixed resolution protein models

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

  2. Fully Atomistic Computational Cost Mixed Resolution Fully coarse grained Quality of the Model 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

  3. 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°

  4. 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)

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

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

  7. 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

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