Molecular Modeling on SYBYL
BL5203
This assignment is for the Lab session on 17 February 2005

Assignment:
Conduct 3D graphics, molecular mechanics and docking study of a protein (HIV-1 protease) and a ligand by using SYBYL.
 
 

• 3D graphics of a protein:

• Type in UNIX command: " sybyl"
• Load a protein:
  • File=>Read=>(select protein.pdb)=>OK=>YES.
• Display the protein in Ribbon representation:
  • View=>Biopolymer Display=>Shaded Ribbon=>All=>OK=>OK.
• Highlight active residues ASP29 and ASP30 by spacefill representation:
  • View=>Mixed Rendering=>Substructures=>(select ASP29, ASP30 from both chain A and B)=>OK=>(select spacefill)=>OK.
• Print the graphics:
  • Type your name(s) in SYBYL window: View=>Annotation=>A=>(click a site) => type your name in
  • File=>Print=>Plotter/Printer Output=>Picture Type: Wire Frame=>(select lab3)=>Print&Close
• Delete the protein:
  • Build/Edit=>Zap (delete) Molecule.
  
   
• Molecular modeling of a drug

• Load a drug:
  • File=>Read=>(select ligand.pdb)=>OK=>YES.
• Add hydrogens to this drug:
  • Build/Edit=>Add=>Hydrogens
• Load charges to this drug:
• Compute=>Charges=>Gaisteiger-Huckel=>No
• Conduct molecular mechanics computation to find lowest potential energy conformation for this drug:
• Use Compute=>Minimize to conduct molecular mechanics computation.
• Use the following parameters:
  • Max Iterations: 1000
• Leave the rest of parameters as default.
• Print out the minimized 3D structure by the following procedure:
  • Type your name(s) in SYBYL window
  • File=>Print=>Plotter/Printer Output=>Picture Type: Ball & Stick=>(select lab3)=>Print&Close
• Determine molecular surface of this drug by the following procedures:
  • View=>Molcad Surfaces=>molecular surface => Create=>Type:Connolly.
  • Explore difference representation modes. You can generate very cool pictures for this drug!
  • Delete this drug.

• Ligand-protein docking by using SYBYL

• Load protein (protein.pdb) and ligand (ligand.pdb). It is recommended that protein be loaded first.
• Start docking by the following procedures:
  • Compute=>Flexidock=>Create An Input File=>OK
  • Close the No Pocket Defined window.
  • In Protein Display Options window, click Define Pocket.
  • In Atom Expression window:
    • Replace M1(0) with M1(957)
    • Click OK.
  • In Protein Display Options window, increase the radius to 10.
  • In Set Up Flexidock window, go through the check list to
    • remove water
    • add hydrogens and charges
    • choose rotatable bonds (use: Add=>All=>OK)
    • mark H-bond sites (use Add=>All=>OK on every item in Defining H-bond Sites window)
    • Position the ligand inside the cavity (you may wish to turn on shaded ribbon for protein to see the cavity better)
    • Type in "hiv", then click on Write Out Flexidock ... and Flexidock It=>OK=>OK=>OK
  • Close Flexidock window
  • Delete both protein and drug
• View docking results
  • File=>Molecular Spreadsheet=>New=>Database=>OK
    • Select hiv.mdb
    • Click Open
  • Select the first row
    • Edit=>Delete
  • File=>Import
    • Select Custom in the Format option menu
    • Click on [...] button next to that option menu
      • Press the check boxes for Labels for both row and columns
      • Click OK
    • Press [...] next to the File Field
      • Change directory to hiv.mdb
      • Select hiv.txt
      • Press OK
    • Press Import
• View docked structure
  • File=>Database=>Open
    • Select hiv.mdb
    • Click Open=>OK
  • File=>Database=>Get Molecule
    • Select HIV0001 (or select the molecule with the lowest energy)
    • Click OK
  • Print the graphics:
    • Type your name(s) in SYBYL window: View=>Annotation=>A=>(click a site).
    • File=>Print=>Plotter/Printer Output=>Picture Type: Wire Frame=>(select lab3)=>Print&Close
      (You may wish to add various backgrounds like shaded ribbon for protein and spacefill for ligand before printing)