Abstract

The standard view is that each protein’s amino acid sequence provides the information for it to fold into a specific 3D structure, and the active site formed within this structure enables function. Indeed, current biology and biochemical textbooks suggest that virtually all proteins act via this sequence-to-structure-to-function paradigm. These views are correct for enzymes, which function as catalysts that accelerate chemical reactions. But a cell is not just an unregulated bag of enzyme-catalyzed chemical reactions. Biological processes, such as cell division, development of different cell types, etc. require a coordinated regulation and organization of the various cellular components and compartments as well as regulation of the various chemical reactions. These regulatory functions involve proteins that interact with each other, with nucleic acids, and with a wide variety of other cellular components via complex networks. These regulatory functions can also involve scaffolds and molecular machines. We have used computational and bioinformatics methods to show that the regulatory signaling interactions in cells depend not only on protein 3D structure, but also depend on lack of 3D structure as well. For signaling proteins, as well as for those involved in scaffolds and machines, we propose a new general paradigm, given in short as sequence-to-flexible-ensemble-to-function. We will illustrate these ideas by providing a background based on bioinformatics approaches and then by providing a number of specific, well studied examples that directly illustrate the points being made.