Jmol/Cavities pockets and tunnels

Jmol can find and display cavities, pockets, and tunnels as isosurfaces.

Definitions

• Cavities are open spaces within a macromolecule, large enough to contain a water molecule, or much larger. The term "cavity" is sometimes used to include pockets and tunnels, but in a stricter usage, it means a space with no openings ("mouths") to the outside surface of the molecule. Jmol's terminology for the stricter usage is "interior cavity".
• Pockets are depressions (concavities) in the surface, or open spaces within the molecule having a single connection ("mouth") to the outside surface of the molecule. They are analogous to bowls and bottles.
• Tunnels or channels are open spaces within the molecule that have two or more connections ("mouths") to the outside surface of the molecule.

Speed of Rendering

If you use the isosurface commands below, do so in the Jmol Java application, not in JSmol in Proteopedia. Depending on the size of the molecule, cavity isosurface commands take about a minute to complete in the Java application, which is many times faster than JSmol. You would have to wait many minutes for completion in JSmol.

Saving Pre-Calculated Isosurfaces

In order to speed up the green links below, the isosurfaces were pre-calculated in the Jmol Java application and then saved into .jvxl (Jmol voxel) files (and uploaded to Proteopedia). These can be quickly loaded without re-computing the isosurfaces. After a cavity isosurface command has completed, the calculated surfaces can be saved with the Jmol command

write filename.jvxl

Later, you can load the saved isosurfaces without re-calculating them using the command

isosurface filename.jvxl

Generating Cavity Isosurfaces

The Jmol commands for generating cavity isosurfaces will be found in the Jmol/JSmol Interacive Scripting Documention under isosurfaces: molecular/solvent surfaces. Near the bottom of that very long section, important commands for after the cavity isosurfaces are calculated:

• isosurface area set (integer) reports the surface area of one isosurface in Ų.
• isosurface delete to clear existing isosurfaces before a new calculation.
• isosurface set (integer) displays just one of the isosurfaces.
• isosurface set 0 displays all of the isosurfaces.
• isosurface volume set (integer) reports the volume of one isosurface in ų.

Small Cavities Example

.

The coronavirus (SARS-CoV-2 and others) spike protein, in its closed conformation, has

. The smaller one is a potential drug target: here is an explanation. These cavities were rendered with the Jmol command

isosurface minset 100 interior cavity 3.0 10.0

The volumes of these cavities are 5,564 and 1,606 ų.

Below we will show the importance of each part of this command.

The simplest command is

isosurface cavity The green link at the top of this section must be clicked before any of the Show Result buttons in this section will work.

This produces pockets, tunnels, and cavities of all sizes. There are 426 separate surfaces. The largest is a convoluted tunnel with many mouths, volume 60,197 ų.

Increasing the Cavity Probe Radius

Cavity Probe Radius 1.2 Å

First, we will limit the result to interior cavities (excluding tunnels and pockets):

isosurface interior cavity

This generates 212 cavities, ranging in volume from 353 down to 1.9 ų. Comparing this with the initial 2-cavity result (green link above), note that neither of the cavities of interest is here. The largest cavity here is much smaller than the smaller cavity in the initial result. By trial and error, this appears to be because the cavity probe size is too small. The default probe radius is 1.2Å. The distinction between interior cavities and pockets/tunnels is whether the space intersects with an envelope of the molecule. Such an intersection represents a mouth. The default probe radius for the envelope is 10 Å. Quoting from the Jmol documentation, "Smaller numbers for the cavity radius lead to more detailed cavities; smaller numbers for the envelope radius lead to cavities that are more internal and extend less toward the outer edge of the molecule." A minimum volume of 1.9 ų is puzzling since it is smaller than the volume of the spherical probe: 1.2 Å is the default radius; spherical probe volume is 7.2 ų. At least no negative volumes are reported.

Cavity Probe Radius 2.0 Å

Increasing the cavity probe radius to 2.0 Å still does not display the cavities of interest (not shown). 44 separate cavities are displayed. Of concern is that most have volumes much less than the spherical volume of the probe (33.5 Å^3), and it is not clear how a cavity smaller than the probe can be detected. Of further concern is that several cavities report negative volumes.

Cavity Probe Radius 2.6 Å

Increasing the cavity probe radius to 2.6 Å finally displays the smaller cavity of interest, but not the larger.

isosurface interior cavity 2.6 10.0

This cavity probe radius gives a volume of 1,855 ų for the smaller cavity of interest, 16% larger than with the 3.0 Šprobe. 10 cavities are reported. The volume of the smallest is reported to be 0.10 ų, and the next-to-smallest, 30.3 ų. The spherical volume of this probe is 73.6 ų.

Cavity Probe Radius 3.0 Å

Increasing the cavity probe radius to 3.0 Å finally shows both cavities of interest.

isosurface interior cavity 3.0 10.0

However there are two smaller cavities that are not of interest. To avoid these, we can specify a minimum number of triangles for cavity surfaces with the parameter minset. Using "minset 100" (value determined by trial and error), we arrive at the command shown at the beginning, which shows only the two cavities of interest. Using "minset 50" eliminated only the smaller of the two unwanted cavities.

Summary of Volumes

The volumes of the two cavities of interest for 6zgi are reported by Jmol as follows:

Reducing the Envelope Probe Radius

We have used the default envelope probe radius of 10.0 Å in all the above examples. If it is reduced to 7.0, the two cavities of interest fail to be displayed [not shown]. This is presumably because a more detailed envelope with more indentations created mouths in the two cavities of interest, rendering them pockets or tunnels, rather than interior cavities with no mouths. If it is reduced to 3.0 Å, no cavities are displayed [not shown]. Two are reported with negative volumes of -560.8 and -3.3. The maximum envelope probe radius allowed by Jmol is 10.0.

Large Cavity Example

The E. coli phosphatase KdsC is an 8-chain homo-octamer. An X-ray structure, 3hyc, reveals a large central cavity, approximately 35 Å in diameter. This cavity connects to the surface with four "mouth" openings, each about 10-12 Å in diameter.