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

Abstract

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−1 compared with the reference 10 seconds−1. 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.