On Unjustifiably Misrepresenting the EVB Approach While Simultaneously Adopting It

Abstract

In recent years, the EVB has become a widely used tool in the QM/MM modeling of reactions in condensed phases and in biological systems, with ever increasing popularity. However, despite the fact that its power and validity have been repeatedly established since 1980, a recent work (Valero et al., J. Chem. Theory. Comput. 5 (2009), 1) has strongly criticized this approach, while overlooking the fact that one of the authors is effectively using it themselves for both gas-phase and solution studies. Here, we have responded to the most serious unjustified assertions of that paper, covering both the more problematic aspects of their work as well as the more complex scientific aspects. Additionally, we have demonstrated that the poor EVB results shown in Valero et al. which where presented as verification of the unreliability of the EVB model were in fact obtained by the use of incorrect parameters. Keywords EVB; Dehalogenase; MOVB; Energy SurfaceIn recent years, the EVB has become a widely used tool in the QM/MM modeling of reactions in condensed phases and in biological systems, and, despite initial skepticism, its power and validity have been repeatedly established since 1980. In some respects, the widespread adoption of the EVB has been the best proof of its validity (see Ref. 1 for further details). Unfortunately, a recent work2 by Truhlar, Gao and their coworkers has strongly criticized the EVB approach, while overlooking the fact that one of the authors is using an effectively identical adaptation himself for both gas phase3 and solution studies4. Here, we provide clarification of the most problematic claims of the paper, and the implications thereof. We will start by first establishing the ethical issues and then move on to the more complex scientific aspects. I. The Main Criticism of the EVB Approach is Apparently IncorrectRef. 2 is a lengthy work, which is presented as "Perspective" on diabatic models of chemical reactivity. On the surface, this work presents six different two-state approaches, one of which is the EVB. However, a close examination of this work will very quickly establish that its main aim is to undermine the validity of the EVB approach. We base this belief not on the fact that

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

“…56 This issue has already been discussed in great length in ref. 57, so here we will only highlight the most problematic points.…”

“…Namely, the most serious incorrect criticisms of the EVB approach in this work can be grouped into five categories: (i) an attempt to reproduce our EVB gas-phase surface (in order to “show” that this is a problematic surface) while using incorrect parameters, which resulted in an incorrect surface that has little to do with the actual EVB surface as discussed in section III.1 (though we should point out that the provision of computational material demonstrating why this EVB surface is erroneous on our website, see section “EVB Verification” on http://futura.usc.edu, has resulted in the retraction of all data pertaining to this EVB surface); (ii) claims that the EVB solution results are irreproducible when the approach used to try to reproduce them is actually incorrect, as was discussed in detail in ref. 57; (iii) claims that the EVB cannot calculate “detailed rate quantities such as kinetic isotope effects that require an accurate treatment of the potential energy surface, zero-point energy (ZPE), and quantum mechanical tunneling”, whereas there are examples of the accurate calculation of all these properties in the literature that the authors neglect to cite; this issue was discussed in detail in ref. 57; (iv) claims that the EVB has never been parameterized to the ab initio surface, where this was done repeatedly (starting in 1988), and has been clarified in our papers in addressing the authors’ allegations; and (v) Questioning the EVB usage of orthogonalized diabatic states and solvent-independent off-diagonal elements, while ignoring the fact that a CDFT study 58 has established the validity of such an approximation.…”

“…It should be noted that this review has been presented at a time when the most senior author of ref. 54 has recently introduced an approach (which he calls the electrostatically embedded multi-configurational molecular mechanics (MCMM) approach 56 ), which, for all intents and purposes, is identical to the EVB approach, as was discussed in our recent Centennial Article for The Journal of Physical Chemistry 5 and in ref. 57.…”

“…54 is factually incorrect on numerous grounds (as we have discussed in detail elsewhere 57 ), nevertheless the fact that such a perspective was even written provides an instructive example of the growing appreciation of the power of the EVB, as well as misunderstanding of the fact that the foundations of the EVB are quite rigorous. In light of the significant errors in this perspective, we have highlighted some of the key problems below, in order to prevent confusion for readers who are unfamiliar with the field.…”

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

“…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.…”