GLOBAL-MMX (GMMX) is a steric energy minimization program which uses the currently selected force field to search for the global energy minimum and other low energy local minima. Processing by GMMX is done in two stages. The first stages randomly searches over the selected rings and rotatable bonds and keeps all conformers within 3.5 Kcal of the lowest energy conformer found (Eminim) during the minimization. The second cycle reminimizes the structures found in the first cycle and keeps only those which are within 3.0 Kcal of the lowest energy conformer. The default energy windows for the two cycles can be changed. In addition to an output file containing the coordinates of the final structures, a textual summary file called '<OUTPUT_FILENAME>.pkm' is produced which lists the energy and Boltzmann distribution of each low energy conformation. This file may also include a listing of query operations (PMR coupling constants, distances, angles, and dihedrals) for each structure as well as a Boltzmann averaged summary.
Although the conformational searching techniques that follow are unique in their approach, the methods described by the Still group (see M. Saunders, K.N. Houk, Y-D Wu, W.C. Still, M. Lipton, G. Chang, and W. Guida J. Am. Chem. Soc. 112, 1419 (1990) and references to previous work cited there in.) were the inspirational source for this work. The search techniques in GMMX are based on the methods used in BAKMDL, developed by Professor Kosta Steliou of Boston University, and ported to the MMX force field by Mark Midland of UC Riverside and Joe Gajewski and Kevin Gilbert of Indiana University. We wish to thank Professors Still and Steliou for sharing with us unpublished work and code that greatly enhanced our routines.
Conformational space can be searched by GMMX in three ways. These are the Mixed method, the Bonds method and the Cartesian method. The Bonds method randomly selects a subset of the bonds designated by the user for rotation. Bond rotation can cause large changes in the shape of a molecule. The Cartesian method randomly moves a subset of all heavy and nonvolatile atoms in 3d space causing small changes in the shape of the molecule. The Mixed method alternates between the Bonds and Cartesian methods and is the preferred method. This procedure is especially efficient with cyclic structures having side chains. You may select ring bonds for rotation as well as the side chain bonds but restricting the bond selection to the side chain bonds usually is all that is necessary if only 3 to 7 member rings are present. The coordinate (Cartesians) movements will apply to the entire structure.
When
Conformational Searching is first selected from the Compute Menu a
dialog box will be presented as shown above. This dialog box controls
the setup and running of GMMX. Items that can be set directly in this
dialog include the jobname, the search method (bonds, coordinates or
both (default)), and the energy windows for the first and second
cycles. The buttons Setup Rings, Setup Bonds, Comparison Method,
Setup Queries, Options, and Read Job all call up further dialog boxes
to setup the various options. Save Job allows the user to save
a file of the current GMMX options, and Read Job reads this file.
Run GMMX starts the first cycle processing while Run 2nd
Cycle starts the job in the second cycle, which
presumes that a file of structures saved from the first cycle is
available.
The Job File names must be set before any search can be done. Use the Set Job Files button to bring up a Save File Dialog and navigate to a directory where you want to save the output files and then enter the name for this job. The input structure file and all the output structure file will be saved in this directory with the name you input.
GMMX will automatically search for all rings in the current structure and the results will be listed in a scrolling list window. To search on a particular ring select that ring from the list of rings and the select the Add button. In molecules containing fused or multi-cyclic ring systems all possible permutations of the rings will be listed. Thus trans decalin will have entries for two six membered rings and one ten membered ring. Care should be taken in selecting the correct ring entry to search. During the search the ring will be broken between the first two atoms of the Atom Number list. These are displayed as Closure Atom 1 and 2. The Closure Atoms may be edited but they must be adjacent atoms.
Additional Ring Information
For each ring defined, GMMX will calculate closure angles and a closure window. Again, the user can accept these values or enter others. Within GMMX each bond is randomly rotated by each angle in the resolution set. The newly created geometry is then analyzed to see if each ring can be reclosed within the defined limits of closure. It is checked for bad 1,5 C-C VDW interactions and trans annular interactions. Structures with up to 2 additional bad 1,5 C-C VDW interactions beyond the original structure may be kept. The structure is also screened for epimerization and all other constraint criteria such as distances, dihedral angles etc. imposed during the interactive procedure. If all the constraint criteria are satisfied, the conformer is processed by GMMX.
To
designate rotatable bonds select the Setup Bonds option in the dialog
box. A new dialog box will be shown. The atom numbers of the
rotatable bond can be entered in the edit boxes. When the ADD button
is selected the atom numbers are read and checked to see that a bond
exists between the two atoms. If a bond is found then the default
rotation increment for this bond is then determined and the bond is
added to the scrolling list of bonds for searching. To delete a bond,
select the bond from the scrolling list and then select Delete.
Bond Resolution
If the bond is an ester or an amide, the resolution set will have two angles (0 and 180 degrees). If the bond is an SP3-SP3 bond, then three angles are used (0, 120, and 240 degrees). If the bond is SP3-SP2, twelve angles are considered (0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, and 330). If the bond is SP2-SP2, 6 angles are chosen (0, 60, 120, 180, 240, and 300). Finally, if the bond is a ring bond, then if the ring is 10 atoms or less, the resolution set will have 12 angles of 30-degree increments as above and if it is 11 atoms or more, 6 angles of 60-degree increments will be used. The user can override these default settings (except for no-rotatable bonds) and enter their own values.
The
Setup Queries dialog box allows one to specify query information for
the second cycle. Clicking on the four options will bring up
dialog boxes for entering atom numbers. For distances the atom
numbers must be entered in sets of 2, for angles sets of 3, for
dihedrals sets of 4 and for coupling constants sets of 2. This
process may be automated by performing the query on the structure on
the screen. This may be done prior to setting up GMMX or while
the main GMMX dialog box is on the screen. Use Query on the
Draw Tools. When one of the four options is selected, the query
information will appear in a scroll list. The final output
file, jobname2.pkm, will contain a list of the queries for each
structure as well as a summary total based on a Boltzmann average.
The
Comparison Method dialog box allows one to choose various options for
structural comparisons during the search. The default is to compare
all nonvolatile atoms. Nonvolatile atoms are those that are not
removed in an H/AD operation, i.e. all heavy atoms and hydrogens on O
or N. A set of specific atoms may be compared by clicking the
Specific non-volatile atoms box and using SELA to select the atoms
for comparison. The default comparison routine uses a fast analytical
method during the first cycle and a slower but more accurate method
during the second run. It is usually better to err on the side of
over collecting on the first run and then weed out duplicates on the
second run.
The
Options dialog box allows one to change several options for the
search. Chirality will be checked and enantiomers rejected if the box
is checked. Hydrogen bonding will be on by default. If the system has
pi atoms turned on, a pi calculation will be performed. Note that
this may not be necessary and may require more time for rigid systems
like benzene. By default, structures will be screened for bad 1,5
interactions and rejected if found prior to minimization.
Conformational enantiomers such as the two gauche forms of butane
will be kept. The Boltzmann temperature is used to calculate the
distribution of isomers. The cutoff distance and energy are used
during structure comparisons. During both cycles all structures
within 0.25 kcal/mol of the current structure will be examined.
During the first cycle a structure will be considered to be unique if
any atom is more than 0.25 Angstroms away for the least squares fit.
In the second cycle the RMS average must be greater than 0.25
Angstroms. The search will stop after the lowest energy structure
(emin) has been found 5 times or there are 25 duplicates in a row
without a new structure. However at least 50 structures must be
minimized. The default number of duplicates required is 2.5 times the
number of heavy atoms with a maximum of 50. The search will also stop
if 50,000 structures have been minimized.
Once all the setup is done GMMX can be run. In all methods the original structure is minimized to generate the initial minimum energy conformation. The structure is then modified by either the bonds or Cartesian method and the new conformation is checked for bad-1, 5 interaction, and epimerization. If all the acceptance criteria are satisfied, the structure is minimized. If the minimization yields an energy acceptable conformer that HAS NOT BEEN FOUND BEFORE, it is saved and its geometry is used to spawn a new conformer, otherwise, it is rejected. Only accepted conformers are permitted to carry-on the search. If attempts to create a new conformer fail, based on the acceptance criteria, it is sent back to try again until a NEW ACCEPTABLE conformer is created. Statistical searching on coordinates should be selected whenever a rigid or fused polycyclic system is to be analyzed. If there are side chains then the Mixed procedure should be favored. The Bonds method is best for acyclic structures.
Run GMMX will automatically run the first and second cycle of the search. The second cycle refines the structures found in the first cycle by throwing out unnecessary duplicates and cutting down the energy window. It also performs any Query operations. The structure output files from both searches are kept. You can send the search output through the second cycle at a later time by using this option. The run will use any criteria (such as Query information) which you have selected.
This option will bring up a file-save dialog box. The default file name will be the Job Name entered in the GMMX dialog box. The file save will save <JobName>.pcm and <JobName>.inp files. The inp file contains the name of the pcm structure file and the directions for doing the search. Thus the pcm file cannot be deleted or renamed if you wish to run this job later. The inp file may be read by the DOS or text-based version of GMMX.
This option brings up a file read dialog box and reads the inp file saved in Save Job. All options will be updated to the settings in the job file