How do miniproteins fold?

How does the amino acid sequence of a protein chain determine and maintain its three-dimensional folded state? Answering this question—a key aspect of the protein-folding problem (1)—would help to explain how multiple noncovalent interactions conspire to assemble and stabilize complicated biomolecular structures; to predict protein structure and function from sequence for proteins that cannot be characterized experimentally; and to design new protein structures that do not exist in nature (2). On page 168 of this issue, Rocklin et al. use parallel protein design on a massive scale to create thousands of miniprotein variants and to determine what sequences specify and stabilize these structures (3). The work opens up considerable possibilities for protein folding and design.