Advances in Understanding Enzyme Function by Way of Computational Investigations Correlated with Experimental Observations

In contrast to the classical paradigm of treating enzymes as passive structural scaffolds that bring together and properly orient other participants in the catalyzed reactions, increasing evidences suggest that the internal motions and conformational alterations of intrinsically flexible enzymes play a vital role throughout catalysis. Such a biophysical view, based on a comprehensive survey of the literature, indicates that a number of enzymes contain distinct regions of conserved residues that are in relation to the active site and presumably serve as pathways of energy transfer for the thermodynamic coupling of the surrounding solvent with enzyme catalysis. It means that some particular conformational fluctuations within enzyme structure essentially encode dynamics and the catalytic rate acceleration, that is, enzymatic features that promote function. Certain computational methods are shown to be capable of establishing the underlying hierarchy of motions that drive the conformational and energetic coupling between enzyme and solvent through internal regions of different protein folds. Theoretical studies that deal with the dynamics of enzyme structure are based on molecular mechanics simulations associated with affordable computational costs. This advantage is limited by the fact that enzyme electronic structure is treated as being unaffected throughout the entire simulation. The impossibility of observing the formation or break up of intra- and intermolecular interactions in order to grasp charge transfer means that it is necessary to exploit quantum-chemical methods that allow the change of the electronic structure in the underlying regions of enzyme function. Recent applications of quantum-chemical wave function-based calculations to this problem, being well calibrated relative to experimental observations, are reviewed. Accordingly, new insights into the function of several enzymes, including viral enzymes and those involved in drug metabolism, intracellular signal transduction pathways and cell cycle control, are summarized. Possible trends in further research are discussed.