Modelling Enzymatic Mechanisms with QM/MM Approaches: Current Status and Future Challenges

Abstract

Quantum mechanics/molecular mechanics (QM/MM) methods are presently a well‐established alternative for the study of enzymatic reaction mechanisms. They enable the description of a small part of the enzyme, where reactions take place through QM, while the majority of the thousands of atoms that comprise these biomolecules are handled through MM. While different “flavors” and variations in the QM/MM field exist, this review will focus more on the application of the ONIOM methodology, presenting a fresh perspective on the application of this popular method in light of the growth in computational power and level of sophistication of the different methodologies that it can combine. In addition to a brief presentation of the basic principles behind these methods, this review will discuss different examples of applicability, common choices, practical considerations, and main problems involved, stemming from our experience in this field. Finally, a reflection on the future challenges for the next decade in the QM/MM modeling of enzymatic mechanisms is presented.

From System Modeling to System Analysis: The Impact of Resolution Level and Resolution Distribution in the Computer-Aided Investigation of Biomolecules

“…The first historical applications of hybrid multiscale models of biomolecules trace back to the 1970s, with the works of Warshel and Karplus (1972) and, a few years later, of Warshel and Levitt (1976) . These works, coupling a quantum mechanical and a classical description, led the foundation for the quantum mechanics/molecular mechanics (QM/MM) methodologies ( Amaro and Mulholland, 2018 ; Magalhães et al, 2020 ), whose relevance was recognized by the attribution of the Nobel prize in Chemistry to Karplus, Warshel, and Levitt in 2013. The development of QM/MM approaches opened the way for the coupling of lower resolution levels for the investigation of phenomena happening at increasingly larger length scales.…”

Perspectives on the Role of Enzymatic Biocatalysis for the Degradation of Plastic PET

“…Furthermore, given Pa PETase similarity to Is PETase, reproducing the successful mutations tested on this enzyme could be a promising strategy for enhancing Pa PETase activity, complemented with computational strategies such as molecular dynamics simulations. However, this mechanistic proposal should be strengthened by experimental evidence on the binding mode (e.g., three-dimensional structures of complexed Pa PETase), and computational studies on the active site conformational flexibility through molecular dynamics, in addition to quantum mechanics studies using, for example, a hybrid QM/MM methodologic approach [ 102 , 103 , 104 ].…”

“…There have been no mechanistic proposals for the Fs Cut degradation mechanism of PET. Since the structure and activity of this enzyme is extensively characterized, several computational studies could be confidently employed to resolve the enzymatic mechanism, particularly QM/MM [ 102 , 103 , 104 ]. The existence of high-resolution three-dimensional structures with a TI model substrate is a relevant clue for mechanistic studies and could be used to validate a QM/MM study.…”

New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach

“…On the other hand, the reaction Gibbs free energies (∆G R ) were calculated through the difference between the energy of product and reactant for each step. This computational approach has already been successfully employed to study the catalytic mechanism of several enzymes [56][57][58][59][60][61][62], including proteases [63][64][65].…”