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The isoxazole fragment shown attached to a ligand. The appearance of the atoms is different than a ball-and-stick model. Atoms are identified by bends in the tube. Colored sleeves are used for non-carbon atoms.

Atom identification and selection is part of using the tools in a Foldit small molecule design puzzle, also known as ligand design. Unlike protein puzzles, small molecule puzzles allow selecting individual atoms.

In Fragment Selection, a fragment first appears as a ball-and-stick model. Carbon atoms are shown in black. The ball-and-stick model reverts to the current Foldit view when the fragment selection is completed.

A single hydrogen atom is selected, highlighted with a sphere and a blue halo.

A single carbon atom is selected, and highlighted.

Multiple hydrogen atoms selected.

Selecting atoms[]

The ligand design tool allows selecting atoms. In the original interface, ligand design is a separate mode, available under Modes in the menu bar.

In the new and selection interfaces, ligand design is a tool in the action bar. Clicking on the tool icon shows the ligand design panel. Atom selection is available while the ligand design panel is open. (Atom selection applies only to the ligand, not to the protein.)

In ligand design, clicking on a atom selects it, and adds a sphere and a halo to indicate it's selected. Clicking on a selected atom clears the selection. Clicking on additional atoms adds them to the selection. Unlike segment selection, control-click and shift-click have no effect in atom selection. Under Cleanup Structure, the "clear atom selection" button deselects all atoms.

Adding or replacing atoms using the Atom Selection tool requires first selecting one or more atoms by clicking on them, then picking a new atom (a new chemical element).

Adding fragments using the Fragment Selection tool also requires selecting at least one atom, then selecting a chemcial fragment. The atoms may already be bonded, or they can be reasonably close to each other.

Atom Selection and Fragment Selection are both a two-step process. First, select an existing atom or atoms by clicking on the ligand. Second, select a new atom or fragment by clicking on an icon in the ligand design panel.

Bond Selection requires selecting two adjacent atoms, then selecting a single, double, or triple bond to connect them. Similarly, "delete bond" in the Cleanup Structure requires selecting two bonded atoms.

Identifying atoms[]

Selecting atoms is one part of the problem. Knowing which atoms are which is another part. Designing ligands involves working on smaller scale than designing proteins.

Setting the correct View Options helpful for working at the ligand level. Here are typical recommended options, taken from the description for Puzzle 2074b: VHL ligand design: Round 5b:

  • Set Color: Score/Hydro+CPK
  • Set View Protein: Binding Site or Cartoon Ligand
  • Turn on: Show Clashes, Show Voids, Show bonds (non-protein), Show bondable atoms
  • Turn off: Show exposed, Show bonds (sheet), Show bonds (helix), Show bonds (loop), Show bonds (sidechain)

For proteins, knowing which amino acid occupies a given segment is enough to identify all its atoms, with minor exceptions. Foldit has several view options which help identify the atoms which can participate in hydrogen bonds. While bands can be attached to specific atoms, selections involve an entire segment, generally an amino acid residue.

The segment identification window shows which amino acid occupies a segment. Recipes can also retrieve the amino acid code for each segment.

Finding out the exact composition of a ligand is more difficult.

Unlike ball-and-stick models, Foldit doesn't usually show atoms as spheres. In the cartoon views often seen in Foldit, atoms appear as rounded bends in a tube. Different colored "sleeves" identify the chemical element. A blue sleeve indicates nitrogen, red indicates oxygen, and yellow indicates sulfur. Carbon doesn't have its own color, and is the same color as the tube. Hydrogen appears as a white cap attached to another atom. It may be difficult to distinguish the less common elements, such as fluorine, which has a color similar to the one used for sulfur.

(See the wikipedia article CPK coloring, which shows the same color for fluorine and chlorine. Foldit uses two different colors for F and Cl, but fluorine and sulfur are very close to each other in Foldit's color scheme.)

There's no equivalent to the segment information window in ligand design. Hovering over a ligand atom won't tell you which element it is. Color is is the primary clue.

For players with limited color vision, reliance on color is frustrating. Even for those with normal color vision, things like the "night light" setting in Windows may make color a less reliable guide.

Aside from color, the presence of hydrogen atoms is another clue. For example, replacing a hydrogen atom with sulfur give a yellow atom with a white hydrogen attached. Replacing hydrogen with fluorine also gives a yellowish atom, but it won't have an attached hydrogen.

Recipes can tell how many atoms a ligand contains, but not which atom is which element.

Until Foldit adds some additional features, identifying atoms may involve a certain amount of trial and error.

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