Parameterization of OPLS–AA force field for the conformational analysis of macrocyclic polyketides

Abstract

The parameters for the OPLS–AA potential energy function have been extended to include some functional groups that are present in macrocyclic polyketides. Existing OPLS–AA torsional parameters for alkanes, alcohols, ethers, hemiacetals, esters, and ketoamides were improved based on MP2/aug‐cc‐pVTZ and MP2/aug‐cc‐pVDZ calculations. Nonbonded parameters for the sp³ carbon and oxygen atoms were refined using Monte Carlo simulations of bulk liquids. The resulting force field predicts conformer energies and torsional barriers of alkanes, alcohols, ethers, and hemiacetals with an overall RMS deviation of 0.40 kcal/mol as compared to reference data. Densities of 19 bulk liquids are predicted with an average error of 1.1%, and heats of vaporization are reproduced within 2.4% of experimental values. The force field was used to perform conformational analysis of smaller analogs of the macrocyclic polyketide drug FK506. Structures that adopted low‐energy conformations similar to that of bound FK506 were identified. The results show that a linker of four ketide units constitutes the shortest effector domain that allows binding of the ketide drugs to FKBP proteins. It is proposed that the exact chemical makeup of the effector domain has little influence on the conformational preference of tetraketides. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 977–996, 2002