Merck molecular force field. IV. conformational energies and geometries for MMFF94

This article describes the parameterization and performance of MMFF94 for conformational energies, rotational barriers, and equilibrium torsion angles. It describes the derivation of the torsion parameters from high-quality computational data and characterizes MMFF94's ability to reproduce both computational and experimental data, the latter particularly in relation to MM3. The computational data included: (i) N 250 comparisons of conformational energy based on "MP4SDQ/TZP" calculations (triple-zeta plus polarization calculations at a defined approximation to the highly correlated MP4SDQ level) at MP2/6-31G* geometries; and (ii) N 1200 MP2/TZP comparisons of "torsion profile" structures at geometries derived from MP2/6-31G* geometries. The torsion parameters were derived in restrained least-squares fits that used the complete set of available computational data, thereby ensuring that a fully optimal set of parameters would be obtained. The final parameters reproduce the "MP4SDQ/TZP" and MP2/TZP computational data with root mean square (rms) deviations of 0.31 and 0.50 kcal/mol, respectively. In addition, h4MFF94 reproduces a set of 37 experimental gas-phase and solution conformational energies, enthalpies, and free energies with a rms deviation of 0.38 kcal/mol; for comparison, the "MP4SDQ/TZP" calculations and MM3 each gives a rms deviation of 0.37 kcal/mol. Furthermore, MMFF94 reproduces 28 experimentally determined rotational barriers with a rms deviation of 0.39 kcal/mol. Given the diverse nature of the experimental conformational energies and rotational barriers and the clear indications of experimental error in some cases, the MMFF94 results appear excellent. Nevertheless, MMFF94 encounters somewhat greater difficulty in handling multifunctional compounds that place highly polar functional groups in close proximity, probably because it, like other commonly