Benchmark studies of hydrogen bond governing reactivity of cephalosporins in L1 metallo-β-lactamase: Efficient and reliable QSPR equations

The combined quantum mechanics/molecular mechanics (QM/MM) simulations of equilibrium geometry configurations followed by electron density analysis provide reliable quantitative structure-property relationship equations to estimate the reactivity of compounds in the active sites of enzymes. The main drawback is high computational cost of such calculations. Here, we report on a benchmark study aiming to optimize computational protocol for the accuracy of predictions. We considered an important example of cephalosporin hydrolysis in the active site of L1 metallo-β-lactamase and found that it is important to consider contributions to the one-electron part of the QM Hamiltonian from all MM system rather than using the cutoff of electrostatic interactions. Switching from the reference PBE0-D3/6-31G(d,p) QM protocol to the reduced PBE0-D3/6-31G scheme decreases the number of basis set functions by almost twice, increasing the error of the rate constant estimates up to 18 seconds compared with the reference 10 seconds. Therefore, the QM(PBE0-D3/6-31G)/MM(AMBER) level of theory can be recommended for estimates of cephalosporin reactivity in the search of new antibiotics.