Protein Visualization using SYBYL, BioPolymer and MOLCAD

EXERCISE:  Protein visualization using SYBYL, BioPolymer and MOLCAD

  1. First you are going to read in the PDB file for acetylcholinesterase inhibited by Aricept (E2020):
    • {File} >> {Read...} >> select 1EVE.pdb >> {OK}
    • select CENTER_VIEW >> {OK}
  2. Next you are going to look at the secondary structure of the enzyme:
  3. {Biopolymer} >> {Display} >> {Ribbon/Tube...} >> {All} >> {OK}

Note that if the PDB file had not automatically contained secondary structure assignment information, it would still have been able to generate such a diagram by determining the structural elements on the fly via:

  • {Biopolymer} >> {Assign Secondary Structure...} >> M1: >> {OK}
  • {View} >> {Delete All Backgrounds}
  • You are now going to generate a ribbon structure which is colored according to the structural B-factors associated with the crystal structure. This is a measure of the relative flexibility and mobility of various regions of the structure. Start by coloring the atoms:
  • {Biopolymer} >> {Display} >> {Color by B-Factors...} >> select M1 >> {OK} >> {Yes}
  • {Biopolymer} >> {Display} >> {Shaded Ribbon...} >> {All} >> {OK} >> select BY_ATOM_COLOR >> {OK}
  • Then you will create the ribbon structure:

Red areas are the most flexible ('hot'), while blue are the most rigid ('cold').

  1. {View} >> {Delete All Backgrounds}
  2. The final part of the visualization exercise will be to examine the structure of the enzyme's receptor. First you are going to define a set of atoms within the receptor region by identifying those that are within a radius of 8 Angstroms of the E2020 inhibitor:
    • {Build/Edit} >> {Define} >> {Static Set...} >> select ATOM >> {OK}
    • Select {Substructures...}
    • Scroll down about 60% of the way and select E202001 >> {OK}
    • Select {Sets...}
    • In the "R =" box, type in "8" >> {OK} >> {OK}
    • Type in "receptor" for the Set Name >> {OK} >> {OK}
  3. You are now going to extract the inhibitor from the enzyme, copy it into its own molecular area, and delete the original version from the receptor:
  4. {Build/Edit} >> {Extract} >> {Substuctures...} >> select E202001 >> {OK} >> {OK} >> select M2 >> {OK}
  5. {Build/Edit} >> {Delete} >> make sure that "M1" is selected >> {Substructure...} >> select E202001 >> {OK} >> {OK}

The ligand still appears on screen, but will no longer get in the way of any attempt to map the receptor surface.

  1. You are now going to color all enzyme atoms as follows: acidic = red, basic = blue, hydrophobic = yellow, other = white (this is a fairly standard way to specify them):
    • {View} >> {Color} >> {Atoms...} >> {All} >> {OK} >> select WHITE >> {OK}
    • {View} >> {Color} >> {Atoms...} >> {Sets...} >> select ACIDIC >> {OK} >> {OK} >> select RED >> {OK}
    • {View} >> {Color} >> {Atoms...} >> {Sets...} >> select BASIC >> {OK} >> {OK} >> select BLUE >> {OK}
    • {View} >> {Color} >> {Atoms...} >> {Sets...} >> select HYDROPHOBIC >> {OK} >> {OK} >> select YELLOW >> {OK}
  2. You are now going to create a solvent accessible surface in the receptor region:
  3. {View} >> {MOLCAD Surfaces} >> {Molecular Surfaces...} >> {Create...}
  4. By the "Atoms:" specification text box, click on the {...} button
  5. {Sets...} >> scroll down to the bottom and select "RECEPTOR" >> {OK}
  6. {OK}
  7. {OK}

Note that it's possible to create surface maps for entire enzymes, but that can be quite time consuming.

  1. You are now going to translate the atomic color to the surface and close the MOLCAD widget:
    • Click the "Color: By Atom Color" button on the MOLCAD Surfaces widget
    • {Done}
  2. Finally, for publication quality visualization, it's often desirable to have the ligand represented by something more easily visible than thin sticks:
  3. {View} >> {Color} >> {By Atom Type} >> select M2: >> {OK}
  4. {View} >> {Mixed Rendering...} >> select M2: >> {All} >> {OK} >> select "Ball_and_Stick" for the representation >> {OK}
  5. Click the "Objects" button >> select "M1 MOL_ID: 1;" and "1 D1 Connolly"
  6. Adjust the "Mid Pt" down using the down arrow
  7. You may also wish to rotate the system around in order to get a better idea for how the molecule conforms to the receptor cavity
  8. You may then wish to experiment with using the "Cutplanes" option. This is the 8th button from the top on the left sidebar of the SYBYL window. Once you have clicked thisclick the "Objects" button >> select "
    • M1 MOL_ID: 1;" and "1 D1 Connolly"
    • Adjust the "Mid Pt" down using the down arrow
    • You may also wish to rotate the system around in order to get a better idea for how the molecule conforms to the receptor cavity

CONTACT
David Johnson
emaildkjohnson@ku.edu
Access to more than 40 computational chemistry software programs and databases
High-performance computational tools accelerate drug discovery and minimize costs
Analyze complex, multidimensional data sets to rapidly generate biological insights
KU Today