Despite abundant sequence and structure data, the functions of most gene products still elude us. The Evolutionary Trace (ET) approach to this problem is to focus on functional sites by characterizing their key amino acids. ET combines sequences, evolutionary trees, and structures to reveal the canonical determinants of function. Large-scale studies show that these determinants cluster spatially in the structure and that they match functional sites on proteins surfaces. Their discovery allows experimentalists to rationally design activity through targeted mutagenesis, for example along the G protein-signaling pathway. The scalability and generality of ET further suggest that proteome-wide annotation of functional sites is within reach. The activity of many protein structures may then be traced to narrow sets of relevant amino acids that form “elementary units of function”. From a practical viewpoint, these units can be targeted for identification and design to analyze and manipulate the molecular basis of protein function. From a more theoretical perspective, it appears that widespread occurrence and 3-D spatial clustering of important residues is a general principle, which reflects that evolution acts on, and thereby links, sequence, structure, and function.
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