Large-Scale Density Functional Theory Transition State Searching in Enzymes

Lever, Greg; Cole, D. J. A.; Lonsdale, Richard; Ranaghan, Kara E.; Wales, David J.; Mulholland, Adrian J.; Skylaris, Chris Kriton; Payne, Mike C.

doi:10.1021/jz5018703

Cited by 49 publications

(50 citation statements)

References 65 publications

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“…This type of work is now feasible to understand the energies and forces experienced by biomolecules as full ab initio detail is possible for systems of thousands of atoms, computationally expensive though it may be. One such study enabled calculation of the activation energy of an enzyme through description of the entire enzyme's electronic structure [338], made possible by the linearly scaling density functional theory implementation ONETEP. This kind of electronic structure characterisation may become a powerful tool in the future, as it may enable the properties and functions of biomolecules to be predicted and understood from the electronic distribution [339].…”

Section: Quantum Mechanicsmentioning

confidence: 99%

Single-molecule techniques in biophysics: a review of the progress in methods and applications

et al. 2017

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Single-molecule biophysics has transformed our understanding of biology, but also of the physics of life. More exotic than simple soft matter, biomatter lives far from thermal equilibrium, covering multiple lengths from the nanoscale of single molecules to up to several orders of magnitude higher in cells, tissues and organisms. Biomolecules are often characterized by underlying instability: multiple metastable free energy states exist, separated by levels of just a few multiples of the thermal energy scale k T, where k is the Boltzmann constant and T absolute temperature, implying complex inter-conversion kinetics in the relatively hot, wet environment of active biological matter. A key benefit of single-molecule biophysics techniques is their ability to probe heterogeneity of free energy states across a molecular population, too challenging in general for conventional ensemble average approaches. Parallel developments in experimental and computational techniques have catalysed the birth of multiplexed, correlative techniques to tackle previously intractable biological questions. Experimentally, progress has been driven by improvements in sensitivity and speed of detectors, and the stability and efficiency of light sources, probes and microfluidics. We discuss the motivation and requirements for these recent experiments, including the underpinning mathematics. These methods are broadly divided into tools which detect molecules and those which manipulate them. For the former we discuss the progress of super-resolution microscopy, transformative for addressing many longstanding questions in the life sciences, and for the latter we include progress in 'force spectroscopy' techniques that mechanically perturb molecules. We also consider in silico progress of single-molecule computational physics, and how simulation and experimentation may be drawn together to give a more complete understanding. Increasingly, combinatorial techniques are now used, including correlative atomic force microscopy and fluorescence imaging, to probe questions closer to native physiological behaviour. We identify the trade-offs, limitations and applications of these techniques, and discuss exciting new directions.

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Section: Quantum Mechanicsmentioning

confidence: 99%

Single-molecule techniques in biophysics: a review of the progress in methods and applications

et al. 2017

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“…Despite the need for careful modeling and computational requirements, these methods can offer accurate results in describing chemical reactions in large biomolecular systems, both qualitatively and quantitatively, when comparing with pure QM approaches. Recent work has evidenced progress toward the implementation of coarse‐grained potentials to provide for a better inclusion of average solvent effects in enzyme catalysis, the use of linear‐scaling DFT to further increase the size of QM regions in biomolecular models (or even account for full biomolecular models), or the combination of DFT and ab initio post HF (such as MP2 or SCS‐MP2) to extend the accuracy of the reaction energy profiles of enzyme‐catalyzed reactions . Nevertheless, the description and flexibility of the large environment, or the computational limits to the determination of conformational free‐energy profiles are still current drawbacks; hence several other methodologies comprehending this multiconformational environment are being combined to try to improve the results produced by standard single‐conformation QM/MM methods, in particular when a good‐resolution X‐ray structure cannot be used as a starting point.…”

Section: Different Strategies In the Study Of Reaction Mechanismsmentioning

confidence: 99%

Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms

Sousa

Ribeiro

Neves

et al. 2016

WIREs Comput Mol Sci

157

118

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Quantum mechanics/molecular mechanics (QM/MM) methods offer a very appealing option for the computational study of enzymatic reaction mechanisms, by separating the problem into two parts that can be treated with different computational methods. Hence, in a QM/MM formalism, the part of the system in which catalysis actually occurs and that involves the active site, substrates and directly participating amino acid residues is treated at an adequate quantum mechanical level to describe the chemistry taking place. For the remaining of the enzyme, which does not participate directly in the reaction, but that typically involves a much larger number of atoms, molecular mechanics is employed, traditionally through the application of a biomolecular force field. When applied with care, QM/MM methods can be used with great advantage in comparing, at a structural and energetic level, different mechanistic proposals, discarding mechanistic alternatives and proposing new mechanistic pathways that are consistent with the available experimental data. With time, diverse flavors within the QM/MM methods have emerged, differing in a variety of technical and conceptual aspects. Hence present alternatives differ between additive and subtractive QM/MM schemes, the type of boundary schemes, and the way in which the electrostatic interactions between the two regions are accounted for. Also, single‐conformation QM/MM, multi‐PES approaches, and QM/MM Molecular Dynamics coexist today, each type with its own advantages and limitations. This review focuses on the application of QM/MM methods in the study of enzymatic reaction mechanisms, briefly presenting also the most important technical aspects involved in these calculations. Particular attention is dedicated to the application of the single‐conformation QM/MM, multi‐PES QM/MM studies, and QM/MM‐FEP methods and to the advantages and disadvantages of the different types of QM/MM. Recent breakthroughs are also introduced. A selection of hand‐picked examples is used to illustrate such features. WIREs Comput Mol Sci 2017, 7:e1281. doi: 10.1002/wcms.1281 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis Electronic Structure Theory > Combined QM/MM Methods

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“…Arg90 was found to play a central role, as confirmed by site-directed mutagenesis [10, 11,18,19]. Subsequent computational studies explored the potential reaction path, including chorismate pre-equilibration, and its activation energy [9, [20][21][22][23][24][25][26][27][28][29][30][31][32] as well as the role of individual active site residues [25,33] and solvation [21,[24][25][26]32,34]. For over a decade, there was a heated debate about the question if TS stabilization or ground state destabilization provides the main driving force for the rate enhancement [11,22,31,35,36].…”

mentioning

confidence: 99%

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

et al. 2017

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Chorismate mutase is a well‐known model enzyme, catalyzing the Claisen rearrangement of chorismate to prephenate. Recent high‐resolution crystal structures along the reaction coordinate of this enzyme enabled computational analyses at unprecedented detail. Using quantum chemical simulations, we investigated how the catalytic reaction mechanism is affected by electrostatic and hydrogen‐bond interactions. Our calculations showed that the transition state (TS) was mainly stabilized electrostatically, with Arg90 playing the leading role. The effect was augmented by selective hydrogen‐bond formation to the TS in the wild‐type enzyme, facilitated by a small‐scale local induced fit. We further identified a previously underappreciated water molecule, which separates the negative charges during the reaction. The analysis includes the wild‐type enzyme and a non‐natural enzyme variant, where the catalytic arginine was replaced with an isosteric citrulline residue.

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Large-Scale Density Functional Theory Transition State Searching in Enzymes

Cited by 49 publications

References 65 publications

Single-molecule techniques in biophysics: a review of the progress in methods and applications

Single-molecule techniques in biophysics: a review of the progress in methods and applications

Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

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