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Molecular modeling of protein-ligand interactions: Detailed simulations of a biotin-streptavidin complex

Molecular modeling of protein-ligand interactions: Detailed simulations of a biotin-streptavidin complex. Prof. Terry P. Lybrand Vanderbilt University Center for Structural Biology & Departments of Chemistry and Pharmacology. T. P. Lybrand SURA 2003. Streptavidin.

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Molecular modeling of protein-ligand interactions: Detailed simulations of a biotin-streptavidin complex

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  1. Molecular modeling of protein-ligand interactions: Detailed simulations of a biotin-streptavidin complex Prof. Terry P. Lybrand Vanderbilt University Center for Structural Biology & Departments of Chemistry and Pharmacology T. P. Lybrand SURA 2003

  2. Streptavidin • Protein isolated from Streptomyces species • Binds biotin with extremely high affinity • Tetramer - ~500 amino acids • One biotin binding site per monomer T. P. Lybrand SURA 2003

  3. Biotin • One of the B-complex vitamins • Necessary for CO2 addition reactions in biosynthesis T. P. Lybrand SURA 2003

  4. General Strategy • Protein engineering • Microcalorimetry • X-ray crystallography • Molecular simulation T. P. Lybrand SURA 2003

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  9. Molecular Dynamics • AMBER version for distributed parallel computation (Swanson & Lybrand, J. Comput. Chem.16:1131-40 (1995) T. P. Lybrand SURA 2003

  10. Potential Function T. P. Lybrand SURA 2003

  11. Potential of Mean Force rc is a reaction coordinate that defines a physical path for the process of interest T. P. Lybrand SURA 2003

  12. Calculated vs. Measured Free Energies (Kcal/mol) PMFExpt.* DG˚ 17.0 ± 3.0 18.3 ± 1.0 (DH˚ = 24.5 ± 0.5; TDS = 6.2 ± 0.5) DG‡ 22.0 ± 3.0 24.4 ± 2.4 (DH‡ = 32.0 ± 2.1; TdS‡ = 7.6 ± 2.1) *Chilkoti & Stayton, J. Am. Chem. Soc.117:10622-8 (1995) T. P. Lybrand SURA 2003

  13. T. P. Lybrand SURA 2003

  14. Freitag, Chu, Penzotti, Klumb, To, Le Trong, Lybrand, Stenkamp, & Stayton Proc.Natl.Acad.Sci.USA96:8384-8389 (1999) T. P. Lybrand SURA 2003

  15. Hyre, Amon, Penzotti, LeTrong, Stenkamp, Lybrand, & Stayton NatureStruct.Biol.9:582-585 (2002) T. P. Lybrand SURA 2003

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  20. Conclusions • Detailed simulations can reproduce quantitatively the experimental thermodynamic results • Contributions of specific protein residues to net thermodynamic changes can be characterized • Simulations can provide detailed insight into dynamics of complex formation and dissociation • Specific water molecules may play a crucial role in complex formation and in stabilization of intermediates on the dissociation reaction coordinate • Streptavidin appears to have evolved a “back door” water channel, possibly to facilitate solvent evacuation of the binding site during complex formation T. P. Lybrand SURA 2003

  21. Dr. Julie E. Penzotti Dr. Lynn Amon Dr. David Hyre Dr. Stephanie Freitag Dr. Lisa Klumb Dr. Richard To Dr. Ashok Chilkoti Vano Chu Isolde LeTrong Prof. Patrick Stayton Prof. Ronald Stenkamp NIH NS33290 NIH DK49655 NIH AI44609 NIH GM56307 NSF MCB9405405 ZymoGenetics T. P. Lybrand SURA 2003

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