Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.
Hirvonen, V., Hammond, K., Chudyk, E., Limb, M., Spencer, J., Mulholland, A., & Van der Kamp, M. (2019). An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases. Journal of Chemical Information and Modeling, 59(8), 3365-3369. https://doi.org/10.1021/acs.jcim.9b00442