The tetracycline: Mg 2+ complex: A molecular mechanics force field

Tetracycline (Tc) is an important antibiotic, which binds specifically to the ribosome and several proteins, in the form of a Tc – :Mg 2+ complex. To model Tc:protein and Tc:RNA interactions, we have developed a molecular mechanics force field model of Tc, which is consistent with the CHARMM force field for proteins and nucleic acids. We used structures from the Cambridge Crystallographic Data Base to identify the main Tc conformations that are likely to be present in solution and in biomolecular complexes. A conformational search was also done, using the MM3 force field to perform simulated annealing of Tc. Several resulting, low‐energy structures were optimized with an ab initio model and used in developing the new Tc force field. Atomic charges and Lennard‐Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with Tc at 36 different positions. We considered both a neutral and a zwitterionic Tc form, with and without bound Mg 2+ . The final rms deviation between the ab initio and force field energies, averaged over all forms, was just 0.35 kcal/mol. The model also reproduces the ab initio geometry and flexibility of Tc. As further tests, we did simulations of a Tc crystal, of Tc:Mg 2+ and Tc:Ca 2+ complexes in aqueous solution, and of a solvated complex between Tc:Mg 2+ and the Tet repressor protein (TetR). With slight, ad hoc adjustments, the model can reproduce the experimental, relative, Tc binding affinities of Mg 2+ and Ca 2+ . It performs well for the structure and fluctuations of the Tc:Mg 2+ :TetR complex. The model should therefore be suitable to investigate the interactions of Tc with proteins and RNA. It provides a starting point to parameterize other compounds in the large Tc family. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1517–1533, 2006