“…Such dynamics plays an important role in allowing for enzyme promiscuity, (i.e., the ability of an enzyme to catalyze multiple, chemically distinct reactions, through either substrate, condition or catalytic promiscuity) and protein moonlighting (i.e., the ability of a protein to perform multiple chemically distinct functions). − This, in turn, facilitates enzyme evolvability (the ability of enzymes to acquire new functions), because the introduction of mutations along an evolutionary trajectory can shift the ensemble of conformational states available to an enzyme, allowing it to bind new substrates and facilitate new chemistry. − This is significant also in artificial enzyme evolution, since, frequently, directed evolution studies identify residues far from the active site that have significant impact on activity and function, − likely by changing the conformational ensemble of the enzyme. , In addition, many enzyme scaffolds (in particular, in the case of TIM-barrel fold proteins , ) possess decorating loops that cover the active site, and there is increasing awareness of the role modulating the dynamics of these loops plays in facilitating enzyme evolvability and the emergence of new functions. ,− However, there is a caveat to this: a highly “floppy” enzyme can, on the one hand, sample multiple conformational states, allowing for new chemistry to evolve. , On the other hand, if there is too much “floppiness” in the system, it becomes very hard to achieve specificity in transition-state binding. Therefore, optimizing conformational dynamics during evolution requires both allowing the system to have enough flexibility to allow for new chemistry, while simultaneously dampening nonproductive dynamics that can impair the catalytic activity of the enzyme. , …”