Perspective: Defining and quantifying the role of dynamics in enzyme catalysis

Abstract

Enzymes control chemical reactions that are key to life processes, and allow them to take place on the time scale needed for synchronization between the relevant reaction cycles. In addition to general interest in their biological roles, these proteins present a fundamental scientific puzzle, since the origin of their tremendous catalytic power is still unclear. While many different hypotheses have been put forward to rationalize this, one of the proposals that has become particularly popular in recent years is the idea that dynamical effects contribute to catalysis. Here, we present a critical review of the dynamical idea, considering all reasonable definitions of what does and does not qualify as a dynamical effect. We demonstrate that no dynamical effect (according to these definitions) has ever been experimentally shown to contribute to catalysis. Furthermore, the existence of non-negligible dynamical contributions to catalysis is not supported by consistent theoretical studies. Our review is aimed, in part, at readers with a background in chemical physics and biophysics, and illustrates that despite a substantial body of experimental effort, there has not yet been any study that consistently established a connection between an enzyme’s conformational dynamics and a significant increase in the catalytic contribution of the chemical step. We also make the point that the dynamical proposal is not a semantic issue but a well-defined scientific hypothesis with well-defined conclusions.

Conformational dynamics and enzyme evolution

“…The functional roles of such conformational changes include, but are not limited to, the allosteric regulation of enzyme function [2,3], motion necessary to access catalytically competent conformations [4], order-disorder transitions that can be necessary to facilitate efficient chemistry [5,6], and, in the case of catalytically promiscuous enzymes, conformational changes that allow for the catalysis of multiple reactions in the same enzyme [7,8]. The extent to which such functionally important conformational dynamics play a role in promoting enzyme catalysis has been the topic of vigorous debate [9][10][11][12][13][14][15][16][17][18][19]. Even more cryptic is the extent to which conformational diversity plays a role in allowing for enzyme evolvability [20,21], either through the repurposing of existing active sites, or through the emergence of completely new active sites in old enzymes.…”

Catalytic Three‐Component Machinery: Control of Catalytic Activity by Machine Speed

“…[3] It is thus an appealing challenge to systematically use dynamic effects in artificial catalysts to speed up ap articular process. [4,5] Herein, we describe how ad ynamic slider-on-deck system can be coupled to an organocatalyst and how the sliding speed (machine speed) in this threecomponent aggregate impacts catalysis.T he results show clearly the prevalence of kinetic over thermodynamic factors in the liberation of catalyst into solution and highlight the usefulness of dynamic multicomponent machinery.…”

A Study of Electrochemical Sensor Based on BHb-imprinted Magnetic Nanoparticles

“…[1][2][3] However, applications are significantly limited due to low stability and the high cost of biological elements. 4 Therefore, the development of artificial receptors with an affinity and specificity approaching biological receptors is a fundamental challenge in molecular recognition.…”