Towards a barrier height benchmark set for biologically relevant systems

Abstract

We have collected computed barrier heights and reaction energies (and associated model structures) for five enzymes from studies published by Himo and co-workers. Using this data, obtained at the B3LYP/6- 311+G(2d,2p)[LANL2DZ]//B3LYP/6-31G(d,p) level of theory, we then benchmark PM6, PM7, PM7-TS, and DFTB3 and discuss the influence of system size, bulk solvation, and geometry re-optimization on the error. The mean absolute differences (MADs) observed for these five enzyme model systems are similar to those observed for PM6 and PM7 for smaller systems (10–15 kcal/mol), while DFTB results in a MAD that is significantly lower (6 kcal/mol). The MADs for PMx and DFTB3 are each dominated by large errors for a single system and if the system is disregarded the MADs fall to 4–5 kcal/mol. Overall, results for the condensed phase are neither more or less accurate relative to B3LYP than those in the gas phase. With the exception of PM7-TS, the MAD for small and large structural models are very similar, with a maximum deviation of 3 kcal/mol for PM6. Geometry optimization with PM6 shows that for one system this method predicts a different mechanism compared to B3LYP/6-31G(d,p). For the remaining systems, geometry optimization of the large structural model increases the MAD relative to single points, by 2.5 and 1.8 kcal/mol for barriers and reaction energies. For the small structural model, the corresponding MADs decrease by 0.4 and 1.2 kcal/mol, respectively. However, despite these small changes, significant changes in the structures are observed for some systems, such as proton transfer and hydrogen bonding rearrangements. The paper represents the first step in the process of creating a benchmark set of barriers computed for systems that are relatively large and representative of enzymatic reactions, a considerable challenge for any one research group but possible through a concerted effort by the community. We end by outlining steps needed to expand and improve the data set and how other researchers can contribute to the process.

Benchmarking density functional tight binding models for barrier heights and reaction energetics of organic molecules

“…In previous work, DFTB models have been tested using single point energies on structures determined by high‐level QM methods. In this work, we explicitly optimize TS structures with DFTB, using the ADF program package …”

DFT‐D4 counterparts of leading meta‐generalized‐gradient approximation and hybrid density functionals for energetics and geometries

“…The benchmark set of enzymatically catalyzed reactions consists of five chemical problems taken from the literature [73][74][75][76][77][78] but provided with reoptimized structures and accurate DLPNO-CCSD(T) [79] reference energies at the complete-basis-set (CBS) limit in 2019. [40,48] (Table 3).…”

An investigation into the applicability of the semiempirical method PM7 for modeling the catalytic mechanism in the enzyme chymotrypsin

“…An estimate of the accuracy of barrier heights, Table 1, can be obtained from a survey [39] which reported that, for four enzymes that did not contain metal atoms, the mean absolute difference for barrier heights calculated using PM7 compared to the reference method B3LYP/6-311+G(2d,2p) [LANL2DZ]//B3LYP/6-31G(d,p) was 7 kcal mol -1 . An unfortunate consequence of the use of a restricted basis set in semiempirical methods is the reduction in the accuracy of prediction of transition state barrier heights.…”