LAUSR

Significance A common way to establish functional relations across organisms is through sequence conservation. In this study, we show that functional evolution also involves a second level of optimization coded in sequence regions that are generally considered nonconserved: the charge of the hypervariable surfaces of folded proteins. The physicochemical signatures of this protein-surface optimization not only diverge in a phylogenetically consistent way, but also are so systematically organized that they allow for detailed functional classification of organisms across all kingdoms of life. Accordingly, the finding 1) exposes a universal determinant of cellular fitness and 2) presents an alternative method for evolutionary and functional elucidation of organisms that is orthogonal to conventional sequence alignment.