Molecular Dynamics Simulations of the TEM-1 β-Lactamase Complexed with Cephalothin

Herein, we present theoretical results aimed at elucidating the origin of the kinetic preference for penicillins over cephalosporins characteristic of the TEM/SHV subgroup of class A β-lactamases. First, we study the conformational properties of cephalothin showing that the C2-down conformer of the dihydrothiazine ring is preferred over the C2-up one by ~2 kcal/mol in solution (0.4−1.4 kcal/mol in the gas phase). Second, the TEM-1 β-lactamase complexed with cephalothin is investigated by carrying out a molecular dynamics simulation. The ΔG<INF>binding</INF> energy is then estimated using molecular mechanics Poisson−Boltzmann surface area (MM-PBSA) and quantum chemical PBSA (QM-PBSA) computational schemes. The preferential binding of benzylpenicillin over cephalothin is reproduced by the different energetic calculations, which predict relative ΔΔG<INF>binding</INF> energies ranging from 1.8 to 5.7 kcal/mol. The benzylpenicillin/cephalothin ΔΔG<INF>binding</INF> energy is most likely due to the lower efficacy of cephalosporins than that of penicillins in order to simultaneously bind the “carboxylate pocket” and the “oxyanion hole” in the TEM-1 active site.