Challenges in computational studies of enzyme structure, function and dynamics

Abstract

In this review we give an overview of the field of Computational enzymology. We start by describing the birth of the field, with emphasis on the work of the 2013 chemistry Nobel Laureates. We then present key features of the state-of-the-art in the field, showing what theory, accompanied by experiments, has taught us so far about enzymes. We also briefly describe computational methods, such as quantum mechanics-molecular mechanics approaches, reaction coordinate treatment, and free energy simulation approaches. We finalize by discussing open questions and challenges.

Theoretical Studies of the Catalytic Mechanism of the Dihydroxyacetone Kinase

“…3 Numerous research works have been done to understand the origin of the catalytic power of the enzymes. [4][5][6][7][8][9] A deep comprehension of the enzymatic mechanisms, that is, understanding the way in which enzymes catalyse chemical reactions is essential to analyse biochemical processes and can contribute to produce new medicines and catalysts. 10 To achieve this comprehension, one elementary point to consider is the comparison of the enzyme catalysed reaction with the uncatalysed equivalent one (the reaction in aqueous solution).…”

“…10,12 Thus, enzymatic P simulations contribute in the comprehension of the extraordinary rate enhancement in enzymes and are able to elucidate different reaction mechanisms. 6 The reaction free energy barriers obtained in the simulations can be compared with experimental measurements assisting in establishing the mechanism behind the experimental kinetics. In addition, improvements in methods to computationally study the reactions together with the development of new highly parallel computer architectures allow increasingly better to reproduce the chemical reactivity.…”

“…3 Numerosos trabajos de investigación se han realizado para entender el origen del poder catalítico de las enzimas. [4][5][6][7][8][9] Una profunda comprensión de los mecanismos enzimáticos, es decir entender la manera en que las enzimas catalizan reacciones químicas, es esencial para analizar los procesos bioquímicos y puede contribuir a producir nuevas medicinas o nuevos catalizadores. 10 Para alcanzar esta comprensión, un aspecto básico a considerar es la comparación de la reacción catalizada con su equivalente no catalizada, es decir, la reacción en disolución acuosa.…”

“…10,12,14 Así pues, las simulaciones computacionales de los sistemas enzimáticos pueden contribuir a la comprensión del aumento extraordinario de la constante de velocidad que caracteriza las enzimas así como esclarecer los posibles mecanismos de reacción. 6 Las barreras de energía libre de la reacción obtenidas en las simulaciones pueden compararse con medidas experimentales ayudando a establecer el mecanismo que hay detrás de la cinética experimental. Además, las mejoras en los métodos y arquitecturas computacionales permiten reproducir la reactividad química cada vez mejor.…”

“…Apart from these theories, it should be considered other effects which, especially during the last years, has mentioned in the literature to contribute in a relevant way in enzymatic catalysis such as, dynamical effects or tunnelling. 6 These effects are discussed in detail in section 5.5.1.…”