Gustavo Caetano-Anollés and Jay Mittenthal
Version of Record online: 20 JUL 2010 | DOI: 10.1002/bies.201090031
Cover Photograph:The interplay of protein stability and function in sequence space, as discussed by Gustavo Caetano-Anollés and Jay Mittenthal on pages 655–658 of this issue. The grid diagram depicts a multidimensional sequence space (flattened into a two-dimensional view) of protein sequences that change into others by single-point mutations (the third dimension represents thermodynamic stability). All proteins in the grid fold into a same three-dimensional (3D) structure, a four-helix bundle structure typical of cytochrome cb562 (a metalloprotein used to study metal-induced protein stability and homodimerization; PDB entry 3L1M). In the diagram, cytochrome proteins drift in evolution along the grid (colored regions) while folding into the same 3D structure and while searching for increases in protein stability (i.e. dents in the grid). This results in sections of the proteins that are evolutionarily conserved due to constraints imposed by the interplay of stability and function (grey regions close to metal-binding sites in the bundles). Image and concept developed by Derek Caetano-Anollés.