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Puzzle 1432

A small molecule is highlighted by the X-ray tunnel feature. Some of the small molecule tools are visible. Puzzle 1432, shown in the image, was the first Small molecule design puzzle.

Small molecule design puzzles present a protein and a small molecule or ligand. The goal is to find a way to bind the ligand to the protein. That may involve moving the ligand to a different spot on the protein, changing the chemical design of the ligand, or selecting an entirely different ligand.

Unlike other Foldit design puzzles, changes to the protein are limited, but a new set of tools is available for working with small molecules.

Small molecule design was originally referred to as drug design, since the puzzles usually involve designing drugs to target proteins associated with diseases.

Small molecule design puzzles have several variations. Many puzzles allow the small molecule to be designed freely. The tools referenced under ligand design can used. Typically, the protein in these puzzles is completely locked in place. In some cases, a few of the protein's sidechains are unlocked. The Compound Library may be available on these puzzles, offering a Compound Library bonus for small molecule designs which can be built to order.

In another variation, the ligand design features are disabled, and predefined small molecules can be selected using the Ligand Queue. Puzzles with a ligand queue may again allow Compound Library searches to expand the possibilities. These puzzles may offer hundreds of different small molecules. The goal is generally to find a small molecule that binds tightly with the protein target.

Another variation is a reaction design puzzle, where the Reaction Design tool is enabled, but the ligand design features again aren't available. Reaction design involves selecting a "reaction", and one or more "reactants", which combine to form a compound. Depending on how many reactions and reactants there are, this type of puzzle can also involve hundreds of compounds. The reaction design format generally ensures that any compound created can actually be built in the lab. Compound Library searches may also be available on a reaction design puzzle.

Tools[]

Small Molecule Design Everything Bagel

A recent puzzle with many small molecule features in action at once.

Most of the small molecule tools require selecting the ligand segment before the tool can be used. Often, once the tool is open, the ligand can be deselected.

The Segment Information window for the ligand shows the subscores which make up its total score. The Clashing, Bonding, and Ideality scores often show areas for improvement.

Objectives[]

Small molecule design puzzles often have several objectives to highlight potential problems with a given ligand. These objectives typically offer a bonus of 1,000 points when completely satisfied. The bonus decreases when there are problems, and can even go negative. Common objectives are:

For most of these objectives, the bonus awarded is fixed for a given molecule. Changing the molecule's design or picking a different molecule are the only ways to change the bonus for these objectives. Most objectives also have a "show" checkbox that highlights ligand problems. (General objectives like Molecular Weight don't have a "show" option.)

The Torsion Quality objective, on the other hand, can be changed, often by simply shaking or wiggling.

The Compound Library objective can also be changed to award a bonus, if a Compound Library search finds a matching molecule.

View Options[]

The Small Molecule View Options panel has specialized controls, but many of the regular View Options are also relevant:

  • Show bonds (non-protein) option shows hydrogen bonds between the ligand and the protein.
  • Ligand Specific color option shows the ligand with an alternate CPK coloring
  • the Binding Site protein view cuts away parts of the protein that are far from the ligand
  • the Cartoon Ligand protein view offers less dramatic highlighting when the ligand is selected
  • the Show All sidechains helps reveal where sidechains may clash with or bind to the ligand
  • X-ray tunnel for ligand highlights the ligand, cutting cutting away parts of the protein
  • Show bondable atoms highlights hydrogen bond donors and acceptors

Separately from any other view options, the camera controls include adjusting near and far visibility. These adjustments may make it easier to see the relation between the ligand and protein.

The View Presets panel offers the Small-Molecule-Design preset with its own combination of options.

Literature[]

External links[]

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