When challenged to design a protein with only the talaris2013 score function (and no additional rules), Foldit players discovered low-energy models that are unlikely to fold as designed. a, An extended α-helix, composed entirely of lysine and glutamate, has very favourable energies for hydrogen-bonding, electrostatic and backbone torsions, but is unlikely to fold cooperatively into a single stable structure. This type of design is discouraged with the ‘core exists’ rule. b, Owing to their greater surface area, large aromatic sidechains can make more interactions than smaller aliphatic sidechains, even when underpacked or solvent-exposed. This type of design is discouraged with the ‘residue interaction energy’ rule. c, A design with an alanine- and glycine-saturated core can make favourable van der Waals interactions between closely packed backbone atoms; however, the burial of these small sidechains is associated with a weaker hydrophobic effect, and the lack of interdigitation allows exchange between multiple conformations with similar core packing energies (that is, molten globule behaviour). These designs are discouraged with the ‘secondary structure design’ rule.