Characterization of the Reaction Path and Transition States for RNA Transphosphorylation Models from Theory and Experiment

Wong, Kin Yiu; Gu, Hong; Zhang, Shuming; Piccirilli, Joseph A.; Harris, Michael E.; York, Darrin M.

doi:10.1002/ange.201104147

Cited by 9 publications

(38 citation statements)

References 42 publications

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“…The study of ribozymes has recently progressed with several QM/MM studies of the hammerhead ribozyme and related reactions (Wong et al 2011(Wong et al , 2012. One of these works (Wong et al 2011) provided a reasonable free-energy surface, using an AM1-type model.…”

Section: Ribozymes and Ribonucleasementioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Section: Ribozymes and Ribonucleasementioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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“…This complexity is a major factor limiting applications of the KP theory beyond KP1, the original FK approach. Wong 2008;Wong and Gao 2008;Wong, Richard et al 2009;Wong, Gu et al 2012). Hence the multidimensional V effectively reduces to 3N one-dimensional potentials along each normal mode coordinate.…”

Section: Automated Integration-free Path-integral Methodsmentioning

confidence: 99%

“…Furthermore, in contrast to Car-Parrinello MD (CPMD) which is limited to potential energy derived from DFT (Car and Parrinello 1985), our method is independent of how the potential energy functions being constructed. Therefore, by combining it with our novel automated integration-free path-integral (AIF-PI) method together (See Section 5; Wong and Gao 2008;Wong, Richard et al 2009;Wong, Gu et al 2012), we will also be able to compute free-energy barriers, changes of binding energy, pK a values, and isotope effects at an ab initio path integral level (see Section 6).…”

Section: Systematic Ab Initio Molecular Dynamics Approach: Free-energmentioning

confidence: 99%

“…In some important applications of Life and Materials Sciences, such as hydrogen adsorption in carbon nanotechnology, the transport mechanism of hydrated hydroxide ions in aqueous solution, and kinetic isotope effects on a proton-transfer reaction, actually internuclear quantum-statistical effects (e.g., quantization of vibration and quantum tunneling) are not negligible. A popular choice for incorporating such internuclear quantum-statistical effects in the conventional molecular dynamics (MD) or Monte Carlo (MC) simulations (Tanaka, Kanoh et al 2005;Warshel, Olsson et al 2006;Kowalczyk, Gauden et al 2007;Gao, Major et al 2008;Kowalczyk, Gauden et al 2008;Major, Heroux et al 2009;Wong, Gu et al 2012) is using Feynman's path integral (Feynman 1948;Feynman 1966;Kleinert 2004;Brown 2005;Feynman, Hibbs et al 2005). …”

Section: Simulating Quantum Thermodynamics: Feynman's Path Integralmentioning

confidence: 99%

“…theoretical method that combines our novel systematic free-energy expansion approach, based on Zwanzig's free-energy perturbation theory, with our recently developed automated integration-free path-integral method, based on Kleinert's variational perturbation theory, Wong and Gao 2008;Wong, Richard et al 2009;Wong, Gu et al 2012) to perform ab initio path-integral simulations for realistic macromolecules at an affordable computational cost. Since in this new method, we can progressively choose computationally affordable levels of theory, now important physical quantities, e.g., free-energy barrier, change of binding energy, pK a value, and isotope effect, can all be computed at an ab initio path-integral level.…”

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confidence: 99%

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Developing a Systematic Approach for Ab Initio Path-Integral Simulations

Wong¹

2012

Molecular Dynamics - Theoretical Developments and Applications in Nanotechnology and Energy

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Mechanistic Insights into RNA Transphosphorylation from Kinetic Isotope Effects and Linear Free Energy Relationships of Model Reactions

Chen

Giese

Huang

et al. 2014

Chemistry A European J

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Phosphoryl transfer reactions are ubiquitous in biology, and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate-controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition state structure and bonding optimally requires the use of theoretical models. In this work, we apply density-functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2’-O-transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well-studied series of phosphate and phosphorothioate mono-, di- and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non-enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease A, and demonstrate the reaction coordinate-KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes.

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Characterization of the Reaction Path and Transition States for RNA Transphosphorylation Models from Theory and Experiment

Cited by 9 publications

References 42 publications

Why nature really chose phosphate

Why nature really chose phosphate

Developing a Systematic Approach for Ab Initio Path-Integral Simulations

Mechanistic Insights into RNA Transphosphorylation from Kinetic Isotope Effects and Linear Free Energy Relationships of Model Reactions

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