Conformational properties of penicillins: Quantum chemical calculations and molecular dynamics simulations of benzylpenicillin

Herein, we present theoretical results on the conformational properties of benzylpenicillin, which are characterized by means of quantum chemical calculations (MP2/6‐31G* and B3LYP/6‐31G*) and classical molecular dynamics simulations (5 ns) both in the gas phase and in aqueous solution. In the gas phase, the benzylpenicillin conformer in which the thiazolidine ring has the carboxylate group oriented axially is the most favored one. Both intramolecular CH · · · O and dispersion interactions contribute to stabilize the axial conformer with respect to the equatorial one. In aqueous solution, a molecular dynamics simulation predicts a relative population of the axial:equatorial conformers of 0.70:0.30 in consonance with NMR experimental data. Overall, the quantum chemical calculations as well as the simulations give insight into substituent effects, the conformational dynamics of benzylpenicillin, the frequency of ring‐puckering motions, and the correlation of side chain and ring‐puckering motions. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1864–1873, 2003