Systematic Parameterization and Simulation of Boronic Acid-β-Lactamase Aqueous Solution in Developing the ABEEMσπ Polarizable Force Field.

Boronic acid, an inhibitor of β-lactamase, has begun to be applied to the treatment of biological infections and tumors. Scientists are working to develop new and more effective boronic acid. Molecular dynamics (MD) simulation provides a powerful auxiliary tool for drug design. However, the current force fields have no boron-related parameters. In this work, an atom-bond electronegativity equalization method at the σπ level (ABEEMσπ) polarizable force field (ABEEMσπ PFF) of boronic acid and β-lactamase has been developed to determine the potential functions and parameters. The interaction between boron and serine in β-lactamase is regarded as a bonded mode. The interaction between them is simulated by the Morse potential energy function, which is close to the experimental change of the stretching potential energy in a large range. The potential energy surfaces of the bond length, bond angle, and dihedral angle of boronic acid-β-lactamase have the same stability point and change trend as M06-2X/6-311G**. For 47 boronic acid-β-lactamase training molecules, the linear correlation coefficient () of the charge distribution between the ABEEMσπ PFF and HF/STO-3G is greater than 0.96. Attributed to the fact that the charge distribution of the ABEEMσπ PFF can fluctuate with the change of geometry and environment, the polarization effect and charge-transfer effect are well reflected. The binding ability of different boronic acids with the same β-lactamase is different. A total of 10 boronic acid-β-lactamase model molecules and 10 boronic acid-β-lactamase and water complexes are simulated. The order of binding energy of five large model molecules calculated by the ABEEMσπ PFF is consistent with that of the MP2 method. The binding energies of boronic acid-β-lactamase and water complexes are close to those of the MP2 method. The results of MD simulation of five aqueous boronic acid-β-lactamase complexes in the ensemble verify the rationality of boron-related parameters of the ABEEMσπ PFF, which have a good application prospect. This study lays a solid theoretical foundation for further study of the inhibition of boronic acid on β-lactamase.