David Baker - Design of protein structures, functions and assemblies

David Baker - Design of protein structures, functions and assemblies

Foldit scientist David Baker explains protein design

In a Design puzzle, the goal is to create a completely new protein. Players can change at least part of the primary structure of the protein, using the mutate tool to change the amino acids. The secondary structure and overall shape of the protein can also be changed as usual.

The goal of most design puzzles is to create a protein that will fold up on its own the same way that natural proteins do.

Other design puzzles challenge players to develop small proteins that bind to larger proteins.

Standard design puzzlesEdit

In a typical design puzzle, players can design the entire protein. These puzzles typically start as an extended chain. Players can mutate the segments to different amino acids and use all the tools available in other types of puzzles.

Unlike most other puzzles, the results of design puzzles are not proteins which can be found in nature. The end of a design puzzle is only the beginning of the process.

Foldit scientists evaluate player designs using Rosetta@home and other tools. Good designs show an "energy funnel" in their Rosetta@home results, which means the protein should tend to reach a single stable shape on its own.

The best player designs are created in the "wet lab" and subjected to further testing. The goal is for the designed proteins to be grown in the lab, extracted, crystallized, and studied with X-ray crystallography and related techniques.

The ultimate achievement for this type of design is a protein where the shape of the Foldit design closely matches the protein grown in the lab.

Most common design puzzles have titles like "80 Residue Monomer Design", meaning there are 80 residues or segments in a single unit. The number of residues available varies from puzzle to puzzle. In this type of puzzle, all the residues are mutable.

There are also symmetry puzzles, in most cases a variation on a standard design puzzle. A symmetry puzzle involves a "monomer unit", a protein which can be designed normally. There are also one or more copies of the monomer, which change as the monomer changes. The goal is to fit the monomer and the copies together into a stable shape called an oligomer.

Symmetry puzzles typically have names like "65 Residue Symmetric Tetramer" or "60 Residue Symmetric Trimer". A trimer means there are three copies of the protein, a tetramer is four copies. There are also dimers (two copies), pentamers (five copies), and hexamers (six copies).

Binder puzzlesEdit

Binder puzzles are another type of design puzzle. Binder puzzles involve designing small protein units which stick to larger target proteins. In this type of puzzle, the small unit be partially or completely designed, while the target protein is more or less fixed.

The targets of this type of design have included the antibiotic vancommycin, the Ebola and Marburg viruses, and the abnormally folded protein "plaques" found in Alzheimer's disease.

A successful binder design could lead to new drug therapies. In the case of viruses, simply binding to the surface of the virus could prevent the virus from infecting healthy cells. For Alzheimer's disease, binding to the plaques would be a first step toward therapies to either eliminate the plaques or render them harmless.

Early design puzzlesEdit

Early Foldit design puzzles had a variety of goals:

  • the flu virus
  • an enzyme to catalyze Diels-Alder reaction
  • an enzyme for CO2 fixation
  • a improve protein to capture sepsis pathogens

Common player structuresEdit

The foldit paper on Nature from 5 June 2019 describes some commonalities among strctures designed by players. Figure 3 shows common backbone structures (among which are examples of the Cynical Helix Ploy fold and the "alpha-beta hotdog" fold), while figure 4 shows details in how sidechains interact, both in foldit solutions and in experiment. Extended figure 5 goes deeper into what each class of figure 3 solutions look like. You can access the paper via ResearchGate for free. [1]


  1. Brian Koepnick, et al (June 2019). De novo protein design by citizen scientists. Nature 570, 390–394
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