Predicting and designing proteins (2): How evolution became a source of structural information

Imagine comparing the same sentence as it has been copied and edited in many communities for millions of years. Some words change freely. Others remain nearly fixed because changing them destroys the meaning. A third group changes in pairs: when one word is replaced, another tends to change as well because the two must remain compatible. Protein families leave a record with a related structure. Their sequences are not sentences, and evolution is not an author, but patterns of conservation and coordinated substitution contain information about molecular constraints. This insight changed structure prediction because it supplied evidence about residues that are far apart in the written sequence but close together in three-dimensional space. It also created the immediate technical ancestry of AlphaFold: first infer contacts and distances from evolutionary variation, then learn how those geometric constraints fit together. From relatives to alignmentsProteins related by descent are…