The breakthrough in protein structure prediction.

Proteins are the essential agents of all living systems. Even though they are synthesized as linear chains of amino acids, they must assume specific three-dimensional structures in order to manifest their biological activity. These structures are fully specified in their amino acid sequences - and therefore in the nucleotide sequences of their genes. However, the relationship between sequence and structure, known as the protein folding problem, has remained elusive for half a century, despite sustained efforts. To measure progress on this problem, a series of doubly blind, biennial experiments called CASP (critical assessment of structure prediction) were established in 1994. We were part of the assessment team for the most recent CASP experiment, CASP14, where we witnessed an astonishing breakthrough by DeepMind, the leading artificial intelligence laboratory of Alphabet Inc. The models filed by DeepMind's structure prediction team using the program AlphaFold2 were often essentially indistinguishable from experimental structures, leading to a consensus in the community that the structure prediction problem for single protein chains has been solved. Here, we will review the path to CASP14, outline the method employed by AlphaFold2 to the extent revealed, and discuss the implications of this breakthrough for the life sciences.