MERCK MOLECULAR-FORCE FIELD .4. CONFORMATIONAL ENERGIES AND GEOMETRIES FOR MMFF94

This article describes the parameterization and performance of MMFF94 for conformational energies, rotational barriers, and equilibrium tors ion 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 partic ularly in relation to MM3. The computational data included: (i) simila r to 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 geo metries; and (ii) similar to 1200 MP2/TZP comparisons of ''torsion pro file'' structures at geometries derived from MP2/6-31G geometries. Th e torsion parameters were derived in restrained least-squares fits tha t used the complete set of available computational data, thereby ensur ing that a fully optimal set of parameters would be obtained. The fina l parameters reproduce the ''MP4SDQ/TZP'' and MP2/TZP computational da ta with root mean square (rms) deviations of 0.31 and 0.50 kcal/mol, r espectively. In addition, MMFF94 reproduces a set of 37 experimental g as-phase and solution conformational energies, enthalpies, and free en ergies with a rms deviation of 0.38 kcal/mol; for comparison, the ''MP 4SDQ/TZP'' calculations and MM3 each gives a rms deviation of 0.37 kca l/mol. Furthermore, MMFF94 reproduces 28 experimentally determined rot ational barriers with a rms deviation of 0.39 kcal/mol. Given the dive rse 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 tha t place highly polar functional groups in close proximity, probably be cause it, like other commonly used force fields, too greatly simplifie s the description of electrostatic interactions. Some suggestions for enhancements to MMFF94's functional form are discussed. (C) 1996 by Jo hn Wiley & Sons, Inc.