Proteins with weakly funneled energy landscapes challenge the classical structure–function paradigm

Unearthing the origin of incredible acceleration of chemical reaction rates by enzymes has occupied the minds of biochemists and molecular biologists for more than a century (1). The modern paradigm of enzymatic action rests on the ideas presented by Haldane and Pauling, namely, that enzymes selectively stabilize transition states in chemical reactions, thus lowering reaction activation energies (2). The widely held microscopic view of enzymatic catalysis envisions a nearly static enzyme reaction chamber carefully sculpted by evolution to match complementarily the shape and electrostatic surface of the reaction transition state. However, recent NMR experiments have suggested that enzyme active sites are mobile on the microsecond to second time scale, commensurate with the time scales for the corresponding catalytic reactions (3). Single-molecule fluorescent spectroscopy studies also point to nontrivial static and dynamic disorder in enzymatic processes, something that is often masked by ensemble averaging in macroscopic kinetic experiments (4). Even in the light of these findings, the central dogma of modern structural biology has remained largely intact; 3D protein structure determines its function. Indeed, this paradigm has worked wonderfully over many decades to explain numerous biological processes, from enzymatic catalysis to signal transduction. Recent works, however, suggested that from one-sixth to one-third of eukaryotic proteins are either disordered or contain large disordered regions (5, 6), hinting that the traditional interpretation of the structure–function paradigm may be too limiting (6). Disordered proteins regulate many transcriptional and signal transduction processes (7). They even exhibit enzymatic activity, as was recently demonstrated experimentally (8). How this is accomplished in the absence of prearranged 3D structure has not been well understood. In a recent issue of PNAS, Roca et al. (9) have used computer simulations to explain the way a molten globule can accelerate a chemical …