DDG is a measure of binding energy between proteins. In Foldit, DDG is used to measure how well a designed protein "binder" attaches to a known protein target. Foldit binder puzzles may include a DDG score objective to help evaluate a binder design.
DDG compares the free energy when the two proteins are bound together to the free energy when they are separate. A more negative DDG indicates better, more stable, binding. DDG is reported in units of kilocalories per mole, abbreviated as kcal/mole.
Hovering over a displayed DDG value shows a suggested target value. At least initially, puzzles have suggested a value of -40 kcal/mole as goal for DDG.
The displayed value of DDG uses the "E notation" version of scientific notation. A display value like "3.46e-10" means 3.46 times 10-10. This would be an extremely small positive value, where a much larger negative value is desirable.
As described in the Foldit blog post Analysis of Protein Binder Designs, DDG stands for "delta delta G" (ΔΔG), or "the change in the change in G". The G term is the Gibbs free energy, also known as just "Gibbs energy".
The blog post states:
We start by calculating the energy of both proteins in the bound state (ΔGbound), with the binder and target in contact. Then we calculate the energy of both proteins in the unbound state (ΔGunbound), with the binder and target free in solution. The DDG is the difference, or delta (Δ), between these two numbers (ΔGbound - ΔGunbound). If the DDG is negative, it means that the bound state is more stable than the unbound state, so the binder should spontaneously stick to the target.
The score in Foldit is also a measure of free energy. The Foldit score is adjusted so that a higher score actually means a lower (more negative) free energy, meaning a more stable protein. The main reason for this is to make Foldit more appealing as a game, effectively hiding the science.
Since the score in Foldit represents free energy, a rough DDG involves taking the score with the binder near the target (approximating ΔGbound), then moving the binder away from the target using the move tool and taking the score again (ΔGunbound). The difference, ΔGbound - ΔGunbound, is still in Foldit score units, so the more positive the value, the better.
As of its initial release in August 2020, DDG scoring in Foldit is very slow to calculate. A binder puzzle may have a "DDG score" objective, but players must click "run" or "run all" to see its value. There is no "enable" checkbox, meaning the DDG score won't be calculated automatically with the other scores. At this stage, the DDG score is for information only, and does not affect the Foldit score.
The Foldit developers are planning a feature which would allow calculating DDG asynchronously, meaning without affecting interface gameplay. The initial version of DDG causes a delay of several seconds while calculating, effectively causing Foldit to freeze.