The EVB as a quantitative tool for formulating simulations and analyzing biological and chemical reactions

Kamerlin, Shina Caroline Lynn; Warshel, Arieh

doi:10.1039/b907354j

Cited by 98 publications

(108 citation statements)

References 198 publications

(370 reference statements)

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“…The effectiveness of this approach, when it is calibrated on the energetics of the reference solution reaction (e.g., Ref. 165) and then applied to the enzymatic reaction, has been recognized by many workers other than us (see, e.g., Refs. 87, 149, and 166-168 to name just a few examples).…”

Section: Some Background On the Computational Approachesmentioning

confidence: 99%

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

Warshel

Bora

2016

The Journal of Chemical Physics

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187

168

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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.

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Section: Some Background On the Computational Approachesmentioning

confidence: 99%

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

Warshel

Bora

2016

The Journal of Chemical Physics

Self Cite

187

168

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“…We would also like to clarify that arguments about force fields or other computational problems are not useful. Theoretical methods in biophysics should be validated by careful comparison with experiment, by comparison with ab initio surfaces, and by convergence studies, and, as far as the EVB is concerned, it passed such tests long ago [24,[46][47][48], and its validity in determining activation free energies should not be challenged without pointing out real cases where it has not worked and where other approaches performed in a superior way. In a complete contrast to the implications of SABW, the validity of computational analysis of the origins of catalysis cannot be experimentally explored.…”

Section: On the Need Of Calculations Of Many Effectsmentioning

confidence: 99%

Prechemistry barriers and checkpoints do not contribute to fidelity and catalysis as long as they are not rate limiting

et al. 2012

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In the preceding article, ''Perspective: Prechemistry conformational changes in DNA polymerase mechanisms'' contributed by Schlick and coworkers as well as previous studies of these workers (Schlick et al. in Theor Chem Acc 131:1287 [5970][5971][5972][5973][5974][5975] 2004) have argued that the conformational changes preceding the chemical step contribute to DNA synthesis and to the fidelity of DNA polymerases. In one of our previous investigations (Ram Prasad and Warshel in Proteins 79:2900-2919, 2011), we argued and showed that as long as the free energy barriers associated with any of the prechemistry steps are not rate limiting, they could not contribute to the catalysis and then to the fidelity. Though all our arguments are based on exact and well-defined scientific logics, Schlick and coworkers seem to overlook some of the clear conditions in these arguments and in particular the requirement that the chemical step is rate limiting in their arguments that the prechemistry barriers contribute to the catalysis. In fact, as long as the prechemistry steps are not rate limiting, we have shown that the enzymes cannot carry the memory of the previous steps. We also address other potential misunderstandings about several key issues; First, we clarify that it is misleading to relate the prechemistry proposal to the clear fact that the substrate-induced conformational changes determine the final preorganization (the issue is the height of the barrier of the enzyme substrate system and not the trivial fact that the enzyme has to change its structure when the substrate binds). Second, we address the presumed role of dynamical effects in enzyme catalysis and the assumption that any observable should be explored in studies of biological function even if they are not relevant to the given effect. Third, we clarify that the fidelity cannot be explained or quantified by invoking the induced fit or conformational selection effects but by evaluating the free energy contributions to the rate-limiting steps from the structures of the corresponding systems (that of course can reflect the induce fit structural changes). Overall, we put a major emphasis on clarifying what is the prechemistry proposal and thus on trying to force the reader to focus on the only real controversy. We of course dismiss any implication that our studies cannot explore mutational effects as we actually pioneered such computational studies and we clarify that in studies of chemical rates, the focus Editor's Note: This paper and papers by Mulholland AJ, Roitberg AE, Tuñón I (doi:10.1007/s00214-012-1286 and Schlick T, Arora K, Beard WA, Wilson SH (doi:10.1007/s00214-012-1287-7) document and discuss contrasting outlooks on the questions of prechemistry and catalysis in DNA polymerase. All authors were initially provided with one another's manuscripts, at which point opportunities to make revisions were offered, and finally, Mulholland, Roitberg, and Tuñón were given the 'last word' on the revised manuscripts in their role as commentators. The e...

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“…The strength of the EVB approach is its ability to treat chemistry at the cost of classical FF calculation, thus facilitating extensive sampling of the protein environment. The EVB approach has been reviewed extensively over the years, and we refer the interested reader elsewhere [30,51,53,54]. We note that also the EVB approach has been employed in numerous KIE studies of enzymes [55][56][57][58][59][60].…”

Section: Potential Energy Surfacementioning

confidence: 99%