The beginner puzzle Easy Mini Freestyle is an example of a de-novo puzzle.
Players must look for clues to find the best shape for the protein. The clues include the:
The secondary structure predictions are often helpful, but usually not quite perfect. Players are free to try any of the secondary structure prediction tools found on the web.
Generally, hydrophobic segments should be hidden in the core of the protein as much as possible. Hydrophilic segments, especially long hydrophilics like arginine and lysine, are better candidates for the outside of the protein.
Over the years, several players have contributed strategies for folding a de-novo puzzle.