Selecting DFT methods for use in optimizations of enzyme active sites: applications to ONIOM treatments of DNA glycosylases

Abstract

When using a hybrid methodology to treat an enzymatic reaction, many factors contribute to selecting the method for the high-level region, which can be complicated by the presence of dispersion-driven interactions such as π–π stacking. In addition, the proper treatment of the reaction center often requires a large number of heavy atoms to be included in the high-level region, precluding the use of ab initio methods such as MP2 as well as large basis sets, in the optimization step. In the present work, popular DFT methods were tested to identify an appropriate functional for treating the high-level region in ONIOM optimizations of reactions catalyzed by nonmetalloenzymes. Eight different DFT methods (B3LYP, B97-2, MPW1K, MPWB1K, BB1K, B1B95, M06-2X, and ωB97X-D) in combination with four double-ζ quality Pople basis sets were tested for their ability to optimize noncovalent interactions (hydrogen bonding and π–π) and characterize reactions (proton transfer, SN2 hydrolysis, and unimolecular cleavage). Although the primary focus of this study is accurate structure determination, energetics were also examined at both the optimization level of theory, and with triple-ζ quality basis set and select (M06-2X or ωB97X-D) methods. If dispersion-driven interactions exist within the active site, then MPWB1K/6-31G(d,p) or M06-2X/6-31+G(d,p) are recommended for the optimization step with subsequent triple-ζ quality single-point energies. However, since dispersion-corrected functionals (M06-2X and ωB97X-D) generally require diffuse functions to yield appropriate geometries, the possible size of the high-level region is greatly limited with these methods. In contrast, if the model is large enough to recover steric constraints on π–π interactions, then B3LYP with a small basis set performs comparatively well for the optimization step and is significantly less computationally expensive. Interestingly, the functionals that afford the best geometries often do not yield the best energetics, which emphasizes the importance of structural benchmark studies.

Desulfination by 2′-hydroxybiphenyl-2-sulfinate desulfinase proceeds via electrophilic aromatic substitution by the cysteine-27 proton

“…For comparison, the reaction was modeled using additional functionals that have been used for a similar mechanism. 19 , 20 Finally, limitations of the cluster model in reproducing experimental kinetic parameters are discussed.…”

“…The B3LYP functional has reported limitations, including the treatment of dispersion effects. 19 Optimization and frequency calculations for Model 0 were thus repeated using the B3LYP-D3, 33 ω-B97XD, 34 M06-2X, 35 CAM-B3LYP, 36 and MPWB1K 37 functionals to determine which yields the most reasonable geometry and activation energy. The first three functionals include dispersion correction for a better description of hydrogen bond interactions.…”

“…These functionals have been previously used to study the reactions of organosulfur compounds 38 – 40 and proton transfer in small molecules 20 and enzymes. 19 …”

Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation

“…Indeed, we initially tested a variety of functionals and found the results varied considerably. The M06-2X functional has been shown to model the catalytic step in hUNG and other glycosylases with good accuracy334958, but these reports did not include any metal. The M06-2X functional uses a high HF exchange coefficient and describes main group chemistry better than its M06-L counterpart57, however high HF exchange is known to be unfavorable for transition metals.…”

The definitive challenge of forming uncommon pseudo‐π···H–F and C···H–F hydrogen bonds on cyclic and cubic nonpolar hydrocarbons

“…[ 80 ] Among the several types of hybrid functionals, undoubtedly B3LYP is the most popular and has been broadly used by many members of the scientific community. [ 81 ] Besides the traditional comparison between B3LYP and results determined by the Møller‐Plesset second‐order (MP2) level, [ 82 ] the protocol of Perdew, Burke, and Ernzerhof (PBE) for the generalized gradient approximation (GGA) was successfully tested. [ 83 ] With respect to the intermolecular systems stabilized through the hydrogen bond formation, the B2PLYP, B3LYP, and ωB97X‐D approaches have also provided very promising results.…”