Optimising the β-lactam Parameters Using the Force Field Toolkit

In this work we performed force field parameter optimisation for various β-lactams using the Force Field Toolkit (FFTK) and Gaussian calculations. Two problems that users are likely to encounter when optimising other drug molecules are identified. First, inappropriate CGenFF parameters without penalty prediction could cause a difficulty in optimisation. Second, multiple dihedral parameter sets may produce the same molecular mechanics (MM) potentials of similar quality, raising the question on how to choose the right parameter set as the best solution. A systematic protocol incorporating molecular dynamics simulations and a principle for selecting the dihedral phase shifts are introduced. Using the protocol, we then successfully optimised both neutral and anionic forms of penam and of cephem. Our results highlight the importance of selecting proper phase shifts during the dihedral optimisation, and the protocol proposed in this work is beneficial to other users.