The sequence-structure-function paradigm has dominated twentieth century molecular biology. The paradigm tacitly stipulated that for each sequence there exists a single, well-organized protein structure. Yet, to sustain cell life, function requires (i) that there be more than a single structure, (ii) that there be switching between the structures, and (iii) that the structures be incompletely organized. These fundamental tenets called for an updated sequence-conformational ensemble-function paradigm. The powerful energy landscape idea, which is the foundation of modernized molecular biology, imported the conformational ensemble framework from physics and chemistry. This framework embraces the recognition that proteins are dynamic and are always interconverting between conformational states with varying energies. The more stable the conformation the more populated it is. The changes in the populations of the states are required for cell life. As an example, in vivo, under physiological conditions, wild type kinases commonly populate their more stable "closed", inactive, conformations. However, there are minor populations of the "open", ligand-free states. Upon their stabilization, e.g., by high affinity interactions or mutations, their ensembles shift to occupy the active states. Here we discuss the role of conformational propensities in function. We provide multiple examples of diverse systems, including protein kinases, lipid kinases, and Ras GTPases, discuss diverse conformational mechanisms, and provide a broad outlook on protein ensembles in the cell. We propose that the number of molecules in the active state (inactive for repressors), determine protein function, and that the dynamic, relative conformational propensities, rather than the rigid structures, are the hallmark of cell life.
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