MMFF94 Validation Suite
Revised and extended, November 1998
Dr. Thomas A. Halgren
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 above are new entries in this
updated suite. 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). 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 firstname.lastname@example.org; cd to
The additional ERULE structures represent one reason for issuing this updated
validation suite. A second is to correct the MMFF94 results for eight members
of the original suite -- namely, for structures CEWYIM30, DAKCEX, FAPLUD,
GIGCEE, KEPKIZ, SAKGUG, TAPJUP, and VEWZOM. Errors in the original MMFF94 atom
typing for these structures were discovered when individuals attempting to
implement MMFF94 de novo encountered discrepancies with the posted results.
Most such discrepancies had to do with the rules for assignment of aromaticity
in nested ring systems.
In addition to input molecular structure files and auxiliary data, the
validation suite provides output files from computer runs made using Merck's
OPTIMOL molecular-mechanics program 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 -
Structure Input Files
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.
Output Data Files
Results of the MMFF94 calculations are contained in the following three files:
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
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 then 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 following files provide additional information:
The MMFF94.titles file gives short titles for all of the molecules in the 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.
Recommendation and Request
To validate a MMFF94 implementation, it would certainly make sense to choose a
subset of the 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
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.
1. Thomas A. Halgren, J. Comput. Chem., 17, 490-519 (1996).
2. Thomas A. Halgren, J. Comput. Chem., 17, 520-552 (1996).
3. Thomas A. Halgren, J. Comput. Chem., 17, 553-586 (1996).
4. Thomas A. Halgren and Robert B. Nachbar, J. Comput. Chem., 17, 587-615
5. Thomas A. Halgren, J. Comput. Chem., 17, 616-641 (1996).
6. Thomas A. Halgren, J. Comput. Chem., submitted.
7. Thomas A. Halgren, J. Comput. Chem., submitted.
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 will be posted when
this manuscript is published and the MMFF94s parameters have passed into the
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.
As of November 1998, papers 6 and 7 have been reviewed favorably, and it is
anticipated that each will be published in J. Comput. Chem. when revised, and
shortened, versions, have been resubmitted. The input data used in evaluating
force fields in paper 7 are being posted elsewhere on the CCL archives in the
hope that this information will help others to test additional force fields.
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