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 sp(3) 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.

The Millimeter‐ and Submillimeter‐Wave Spectrum of the G t Conformer of n ‐Propanol ( n ‐CH 3 CH 2 CH 2 OH)

“…Because most of the lines assigned to this conformer have been analyzed with an ordinary asymmetric-top Hamiltonian without significant perturbation, the Gt conformer is isolated. This is consistent with the fact that the Gt conformer is calculated to be the global minimum among the five conformers of n-propanol in the most detailed approach used to date ( Kahn & Bruice 2002.…”

“…According to Lotta et al (1984) and Kahn & Bruice (2005), it is likely that four b From Abdurakhmanov et al (1969, 1970. conformers of n-propanol including the Gt form exist within 60 K in energy.…”

“…These studies provide molecular structures and energy dependences on bond distance. More recently, Kahn & Bruice (2002) concluded that the Gt conformer is the global minimum. Later they undertook accurate conformational analyses for ethanol, n-propanol, and iso-propanol by taking into account electron correlation through fourth order with a large basis set (Kahn & Bruice 2005).…”

“…More recently, Kahn & Bruice (2002) concluded that the Gt conformer is the global minimum. Later they undertook accurate conformational analyses for ethanol, n-propanol, and iso-propanol by taking into account electron correlation through fourth order with a large basis set (Kahn & Bruice 2005). They again calculated the Gt conformer to be the global minimum among the five conformers in n-propanol and gave the relative energies of the other conformers including zero-point corrections to be E(Tt) ¼ 35 K, E(Gg) ¼ 50 K, E(T g) ¼ 60 K, and E(Gg 0 ) ¼ 70 K. All of the five conformers are slightly asymmetric prolate tops and their rotational spectra can be analyzed by standard methods for semirigid structures (Gordy & Cook 1984;Watson 1977;Townes & Schawlow 1955) supplemented when necessary for splittings due to internal rotation and other tunneling motions.…”

Probing cations recognized by a crown ether with the 3D-RISM theory. II. 18-crown-6 ether

“…For the crown ether and ions, we employ the parameters from the OPLS force field [24,25]. We use the SPC/E model [26] with the hydrogen Lennard-Jones term (σ = 0.4Å and = 192.5 J/mol) for the water sites.…”