Abstract
It is now common knowledge that enzymes are mobile entities relying on complex atomic-scale dynamics and coordinated conformational events for proper ligand recognition and catalysis. However, the exact role of protein dynamics in enzyme function remains either poorly understood or difficult to interpret. This mini-review intends to reconcile biophysical observations and biological significance by first describing a number of common experimental and computational methodologies employed to characterize atomic-scale residue motions on various timescales in enzymes, and second by illustrating how the knowledge of these motions can be used to describe the functional behavior of enzymes and even act upon it. Two biologically relevant examples will be highlighted, namely the HIV-1 protease and DNA polymerase β enzyme systems.
Highlights
Proteins and enzymes are essential components of living cells
We do not pretend to cover the overwhelming number of theoretical approaches, methodologies, or enzymatic systems that previously illustrated the role of protein dynamics in enzyme function, but instead focus on recent reports where the combination of experimental NMR and computational techniques have emphasized the role of conformational exchange in inhibitor binding (HIV-1 protease) and fidelity in DNA repair through the selection of correct nucleotides (DNA polymerase β)
The intrinsic dynamical properties of enzymes have been shown to impact the catalytic function in a variety of well-characterized systems
Summary
Proteins and enzymes are essential components of living cells. Among a variety of other functions, they act as hormones in cell signaling, protein transporters, antibodies in host defense, etc. We do not pretend to cover the overwhelming number of theoretical approaches, methodologies, or enzymatic systems that previously illustrated the role of protein dynamics in enzyme function, but instead focus on recent reports where the combination of experimental NMR and computational techniques have emphasized the role of conformational exchange in inhibitor binding (HIV-1 protease) and fidelity in DNA repair through the selection of correct nucleotides (DNA polymerase β). One of the most commonly used experiments to characterize local and global conformational events experienced by enzymes on the timescale of their catalytic rate kcat —typically occurring on the order of milliseconds—is the NMR Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiment [29,30,31,32,33] This methodology garnered considerable attention in recent years since motions experienced by enzymes on this physiologically relevant timescale can improve our understanding of catalysis and allostery, as the flexibility events uncovered can be analyzed in light of catalytic events.
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