Quantum Chemical Methods for Modeling Covalent Modification of Biological Thiols

Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semi-empirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the pre-reaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally-optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behaviour of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were easonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that MD simulations using this functional were only stable if a fine integration grid was used. The low-cost semi-empirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics are not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to MVK was calculated using QM/MM MD in an explicit polarizable aqueous solvent.