|Dr. Simon Kearsley|
|Merck and Co., Inc.|
|P.O. Box 2000|
|Rahway, NJ 07065|
The test molecules for this validation suite consist of 698 structures derived from the Cambridge Structural Database maintained by the Cambridge Crystallographic Data Center (which graciously gave permission for their use) plus 63 additional structures for small molecules and ions, for a total of 761. The native CSD structures were modified by assigning single and multiple bonds, affixing formal ionic charges where appropriate, and adding hydrogens to complete the valence. The resultant structures were minimized to a rms gradient of 0.000001 kcal/mol/A on the MMFF94 energy surface, and were then systematically distorted and re-minimized, and then distorted and re-minimized again. The distortion/re-minimizaton steps were taken to reduce the likelihood that any final conformation represents a very shallow local minimum on the MMFF94 surface, as a molecular-mechanics optimizer might conceivably convert such a conformation to a different local minimum and falsely imply a problem with the implementation of MMFF94 being tested.
The validation suite was constructed to test all entries in the MMFF*.PAR parameter files as well as all default-parameter and empirical-rule procedures. The last 8 the 63 additional structures mentioned were added in November 1998 in a previous revision, which also corrected the MMFF94 results for eight members of the original suite -- namely, for structures CEWYIM30, DAKCEX, FAPLUD, GIGCEE, KEPKIZ, SAKGUG, TAPJUP, and VEWZOM. Named ERULE_01 through ERULE_08, these structures are fragments of CSD structures that have been chosen to more fully test the MMFF94 empirical- rule parameter generation procedures than did the original members of the suite (see below).
This revision replaces Tom Halgren with Simon Kearsley as the person to contact at Merck; Tom has moved to Schrodinger, Inc. effective June 1, 1999 (E-mail address: firstname.lastname@example.org). It also specifies the covalent atomic radii used in eq. (18) of ref. 5 (the reference to the origin of those radii may have been incomplete) and lists Pauling electronegativities that would be used in eq (16) (See Auxiliary Data below).
The MMFF94 parameter files can be accessed via an Internet browser at http://journals.wiley.com (select "Journal of Computational Chemistry", then "Supplementary Material", then "Volume 17", then the hyperlink for page 490) or at ftp://ftp.wiley.com/public/journals/jcc/suppmat/17/490. The parameter files can also be accessed by ftp at email@example.com; cd to public/journals/jcc/suppmat/17/490.
In addition to input molecular structure files and auxiliary data, the
suite provides output files from computer runs made using Merck's OPTIMOL
molecular-mechanicsprogram and BatchMin 5.5 from Columbia University.
Note: some files are quite large. Before downloading, you may want to check the sizes listed at the end of this document. You may want to retrieve the compressed tar achive of these files, MMFF94.tar.gz (6.07 MBytes), and unpack it by giving the following UNIX command:
gunzip -c MMFF94.tar.gz | tar xvof -
The following files comprise the input molecular structure data:
|MMFF94.mmd (hypervalent representation only)|
Two formats are provided: mol2, from Tripos, and mmd, the designation used at Merck for BatchMin dat files. We chose these file formats because they are in fairly widespread use and because they allow explicit single and multiple bonds to be designated. Unlike file formats more commonly used at Merck, these formats are limited in that they cannot specify formal-charge information. For this updated suite, however, this information has been included in other files described below.
For the convenience of the user, the mol2 files are presented in two versions. One of these -- MMFF94_dative.mol2 -- uses dative bonding in tetracoordinate sulfur and phosphorous compounds. This representation, for example, treats a sulfonamide as having four single bonds to a +2 sulfur, two of which come from formally negative terminal oxygen atoms. This is the native representation for OPTIMOL, the host program for MMFF. In contrast, the native BatchMin representation features two double bonds from formally neutral oxygen atoms to a formally neutral sulfur, for a (hypervalent) total of six bonds to sulfur; correspondingly "hypervalent" phosphorous compounds have a total of five bonds to phosphorous. This hypervalent bonding pattern is used in the MMFF94_hypervalent.mol2 and MMFF94.mmd files in the validation suite. Note: the atom types in the mol2 files (which were generated by a file conversion procedure developed at Merck) in some cases differ from authentic SYBYL atom types, and therefore should not be relied upon.
Results of the MMFF94 calculations are contained in the following three files:
|MMFF94_opti.log (hypervalent representation only)|
The MMFF94.energies file contains records that list the molecule name, the total MMMFF94 energy computed by OPTIMOL, and the BatchMin 5.5 energy. It should be noted that the BatchMin calculations used a locally modified version of the mmff_setup co-process in which mmff_setup was enhanced to handle the full range of hypervalent -> dative bonding conversions encountered in the validation suite; some cases were not properly accommodated in the distributed BatchMin 5.5 and 6.0 code, but all should be properly handled beginning with BatchMin 6.5 (these internal bonding conversions are needed because the mmff-setup code, which was derived from OPTIMOL, assumes dative bonding). In all cases, no cutoffs on nonbonded interactions were employed and a unit dielectric constant was used. As comment records in the MMFF94.energies file indicate, the OPTIMOL and BatchMin total energies agree to within 0.0001 kcal/mol in all but 15 instances; the largest difference is about 0.0035 kcal/mol. The 15 cases are ones in which a positive or negative formal charge is shared among three atoms of the same MMFF atom type (e.g., the three nitrogens of a guanidinium group); the single-precision division by 3 in the BatchMin run produces a less precise final partial atomic charge and a less accurate total MMFF94 energy.
The MMFF94_bmin.log file contains BatchMin 5.5 output, obtained on a SGI R10000 processor, for single-point energy calculations on input structures read from the MMFF94.mmd file. This log file partitions the total energy into components such as bond stretching, angle-bending, torsion, van der Waals, and electrostatic. It provides the next level of information beyond the simple compilation of total energies found in the MMFF94.energies file.
Finally, the MMFF94_opti.log file contains the output from an OPTIMOL run that employed as input an internal Merck-format data file, MMFF94.ffd, that contains a superset of the information provided in the file MMFF94_dative.mol2 (which was created from it). This log file provides by far the greatest amount of validation information. For each molecule, it begins with information about the atom typing (when rings are present) and lists any invocations of the empirical-rule generation procedures. An initial list section gives the symbolic and numeric MMFF94 types for each atom, together with the MMFF94 formal atomic charge (fractional, rather than integral, when carboxylate anions, guanidinium cations, etc., are present, but usually zero) and partial atomic charge (also provided in the input data files). Next, the total energy and the energy components (bond stretching, ...) are listed. Also shown is the total rms gradient (kcal/mol/A). This quantity is typically small, as befits an energy- minimized structure, but is not zero because the stored coordinates have too little numerical precision. Finally, the analyze section exhaustively lists all interactions of a given type (i.e., all bond-stretching interactions, all angle-bending interactions, ...), and reports both the force-field parameters and the strain energy for the interaction. The notation should be obvious for the most part, but it should be noted that the listed FF CLASS indices are the quantities called bond-type index, angle-type index, etc., in the 1996 J. Comput. Chem. papers (see References). For nonbonded interactions, only pair-wise terms for which the van der Waals repulsion energy is at least 0.01 kcal/mol are listed. Each nonbond output line includes the separate vdW attraction and repulsion components, the Coulombic interaction energy, and the Buffered 14-7 R* and Eps parameters produced by the MMFF combination rules; this data should be more than sufficient to validate an implementation of the MMFF94 nonbonded potential. One cautionary note: eqs.(3) and (4) in the fifth MMFF paper were typeset incorrectly; their counterparts in the first four MMFF papers, however, are correct. The OPTIMOL run was also made on a R10000 processor.
The MMFF94.titles file gives short titles for all of the molecules in the validation suite. The MMFF94.changed-or-new_results file lists the new MMFF94 energies for the eight molecules for which there have been changes in the MMFF94 atom-type assignments. For reference, this file also lists the previously obtained MMFF94 energies; it should be noted that the new energies reflect new MMFF94-optimized geometries as well as new atom types and parameter assignments. This file also lists the MMFF94 energies for the eight added "empirical rule" structures. The MMFF94.empirical_rule_parameters file lists structures for which parameters generated from MMFF94 empirical rules are required and specifies the interactions involved. This file shows that only structures CEWYIM30, KEPKIZ, and OHMW1 from the original suite required such parameter generation. (It should be noted, however, that only the first instance of the generation of a given parameter is reflected in the file; such generated parameters are added to the internal database used by OPTIMOL or BatchMin, and therefore are no longer "missing" if later structures in the suite request them.) Next, the MMFF94.dative_molecules file lists the names of the molecules (129 in number) for which the mol2 files provide contrasting dative and hypervalent structures. (For the mmd file, which always uses the hypervalent representation, the molecule names begin in column 11 of the header cards, immediately following the left square bracket.) Finally, for the sake of completeness the MMFF94.fc_dative and MMFF94.fc_hypervalent files specify the formal ionic charges used in these representations; as indicated previously, this information is not preserved in the mol2 input files, though in most cases it is implicit in the MacroModel atom types (some of which represent Merck extensions) listed in the mmd file.
Though they are seldom if ever actually invoked, the (Pauling) electronegativities that would be used in eq (16) are: H 2.20, He --, Li 0.97, Be 1.47, B 2.01, C 2.5, N 3.07, O 3.5, F 4.10, Ne --, Na 1.01, Mg 1.23, Al 1.47, si 1.74, P 2.06, S 2.44, Cl 2.83, Ar --, K 0.91, Ca 1.04, Sc 1.3, Ti 1.5, V 1.6, Cr 1.6,Mn 1.5, Fe 1.8, Co 1.8, Ni 1.8, Cu 1.9, Zn 1.6, Ga 1.82, Ge 2.02, As 2.20, Se 2.48,Br 2.74, Kr --, Rb 0.89, Sr 0.99, Y 1.3, Zr 1.4, Nb 1.6, Mo 1.8,Tc 1.9, Ru 2.2, Rh 2.2, Pd 2.2, Ag 1.9, Cd 1.7, In 1.49,sn 1.72,Sb 1.82, Te 2.01, I 2.21, Xe --.
To validate a MMFF94 implementation, it would certainly make sense to choose a subset of the validation suite, to convert the mol2 or mmd input data to another format if necessary, and then to begin by computing and comparing total energies to those listed in the MMFF94.energies file; if and when differences are found, the component energies can then be compared to those listed in the MMFF94_bmin.log or MMFF94_opti.log files. Examination of the detailed interaction listings in the OPTIMOL log file might then be needed to diagnose a problem. Ultimately, the entire validation suite should be checked. It is the implementer's choice as to whether to use a dative- or hypervalent-bonding representation for affected compounds, or to support both formats.
We have two requests. The first is that any implementation of MMFF94 be identified simply as MMFF94, and that the name Merck not be used in product literature or in any other way. This is a trademarking issue that our lawyers understand better than I; they are quite adamant about it.
The second request is that any implementation of MMFF94 be explicitly characterized by its authors as to whether it is: (1) partial, or (2) complete. An implementation should not be labeled complete unless it is applicable to all 761 molecules in the test suite and produces total and component energies that match those posted here to within numerical precision. For a partial implementation, published descriptions and product literature should state the degree to which the implementation is applicable to the molecules in the validation suite and the degree to which it produces authentic results for those members of the suite to which it is applicable; a clear statement should also be made as to whether or not the MMFF94 functional form has been fully implemented, as well as whether or not the MMFF94 step-down equivalencing protocol for default parameter assigmnent is fully utilized and whether or not the MMFF94 empirical-rule procedures for parameter generation are faithfully employed.
While a legal agreement authorizes the posting of this public-access validation suite, it prohibits Merck from providing assistance in the development, testing, and implementation of MMFF to any third-party commercial software development company other than academic developers of software. As a matter of courtesy, however, we would appreciate hearing from parties that implement MMFF94 as to how they characterize the completeness and accuracy of their implementation of MMFF94 and as to whether they find discrepancies they believe may reflect errors in the posted results.
Paper 6 describes the derivation and performance of the MMFF94s variant of MMFF94. This variant and the rationale for it are briefly described in papers 1, 3, and 4. A companion MMFF94s validation suite has also been posted; the browser and ftp addresses are the same as those for the present suite except that "MMFF94" is replaced by "MMFF94s".
Paper 7 compares the abilities of MMFF94, MMFF94s, CFF95, CVFF, MSI CHARMm, AMBER*, OPLS*, MM2*, and MM3* (1) to reproduce experimental and theoretical values for conformational energies, and (2) to produce reasonable values and trends for intermolecular-interaction energies and geometries in hydrogen-bonded complexes. Some results are also presented for CHARMM 22. The input data used in evaluating the force fields examined in this paper have also been posted on the CCL archives in the hope that it will help others to test additional force fields; these data can be accessed via a web browser at:
File name Size in Bytes ------------------------------------------ MMFF94.changed-or-new_results 858 MMFF94.dative_molecules 1,080 MMFF94.empirical_rule_parameters 2,453 MMFF94.energies 31,499 MMFF94.fc_dative 32,991 MMFF94.fc_hypervalent 20,575 MMFF94.mmd 2,371,742 MMFF94.tar.gz 6,069,796 MMFF94.titles 53,537 MMFF94_bmin.log 1,181,426 MMFF94_dative.mol2 1,653,121 MMFF94_hypervalent.mol2 1,653,121 MMFF94_opti.log 24,855,731