User:Pakpoom Subsoontorn/Notebook/general reading/2008/10/22: Difference between revisions

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==Design Algorithm==
==Design Algorithm==
# Define PCS that ford van de Waals interaction with the wild-type ligand, replace with ala
# Place a cubic grid for docking ligands with in a convex hull encompassing with wild-type ligand
# Construct an ensemble representing all rotational and internal degrees of freedom of ligand
# Place the rotational ensemble onto the grid and select pose that do not form unfavorable steric interactions and are partially confined within the convex hull. This will be the "doced ligand conformations"
# Rank the docked ensemble by the interaction energy between  the ligands and the receptor
# Calculaate PCS of the top N (~10,000) docked ligands, using DEE




Revision as of 12:00, 23 October 2008

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Computational design of receptor and sensor proteins with novel functions(BioE300a presentation)

Outline

  • Challenges in designing protein
    • Complexity of protein-ligand interaction, too many possibility
    • Two approaches
      • Rational Design
      • Directed Evolution
  • What's new here?
    • Specific goals: changes the specificity of receptors/sensor protein
      • Precursors/ligand (from E.coli PBP): GBP, RBP, ABP, QBP, HBP
      • Targeted ligands: TNT, Serotonin, L-lactate
    • Designing Algorithms
      • Identify amino acid sequences that can form a complementary surface between the protein and the target ligand
      • Dead-end elimination theorem (DEE)
        • Deterministically identifies the global minimum of a semi-empirical potential function of molecular interactions
        • Modified Lennard-Jones potential
        • rapid computation
    • Building new proteins
      • PCR mutagenesis
      • Design outcomes
    • Testing Results:
      • QSAR
      • binding affinities/selectivities
      • Rewiring Pathways
  • Summary/Critique
  • More recent papers

Design Algorithm

  1. Define PCS that ford van de Waals interaction with the wild-type ligand, replace with ala
  2. Place a cubic grid for docking ligands with in a convex hull encompassing with wild-type ligand
  3. Construct an ensemble representing all rotational and internal degrees of freedom of ligand
  4. Place the rotational ensemble onto the grid and select pose that do not form unfavorable steric interactions and are partially confined within the convex hull. This will be the "doced ligand conformations"
  5. Rank the docked ensemble by the interaction energy between the ligands and the receptor
  6. Calculaate PCS of the top N (~10,000) docked ligands, using DEE



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