MERCK MOLECULAR-FORCE FIELD .1. BASIS, FORM, SCOPE, PARAMETERIZATION,AND PERFORMANCE OF MMFF94

This article introduces MMFF94, the initial published version of the M erck molecular force field (MMFF). It describes the objectives set for MMFF, the form it takes, and the range of systems to which it applies . This study also outlines the methodology employed in parameterizing MMFF94 and summarizes its performance in reproducing computational and experimental data. Though similar to MM3 in some respects, MMFF94 dif fers in ways intended to facilitate application to condensed-phase pro cesses in molecular-dynamics simulations. indeed, MMFF94 seeks to achi eve MM3-like accuracy for small molecules in a combined ''organic/prot ein'' force field that is equally applicable to proteins and other sys tems of biological significance. A second distinguishing feature is th at the core portion of MMFF94 has primarily been derived from high-qua lity computational data-ca. 500 molecular structures optimized at the HF/6-31G level, 475 structures optimized at the MP2/6-31G* level, 380 MP2/6-31G structures evaluated at a defined approximation to the MP4 SDQ/TZP level, and 1450 structures partly derived from MP2/6-31G geom etries and evaluated at the MP2/TZP level. A third distinguishing feat ure is that MMFF94 has been parameterized for a wide variety of chemic al systems of interest to organic and medicial chemists, including man y that feature frequently occurring combinations of functional groups for which little, if any, useful experimental data are available. The methodology used in parameterizing MMFF94 represents a fourth distingu ishing feature. Rather than using the common ''functional group'' appr oach, nearly all MMFF parameters have been determined in a mutually co nsistent fashion from the full set of available computational data. MM FF94 reproduces the computational data used in its parameterization ve ry well. In addition, MMFF94 reproduces experimental bond lengths (0.0 14 Angstrom root mean square [rms]), bond angles (1.2 degrees rms), vi brational frequencies (61 cm(-1) rms), conformational energies (0.38 k cal/mol rms), and rotational barriers (0.39 kcal/mol rms) very nearly as well as does MM3 for comparable systems. MMFF94 also describes inte rmolecular interactions in hydrogen-bonded systems in a way that close ly parallels that given by the highly regarded OPLS force field. (C) 1 996 by John Wiley & Sons, Inc.