MULT - MULTiconformer minimization

Perform multiconformer minimization, i.e., delete duplicate structures as defined by the

This command is appropriate only for a file of different conformations of the same molecule as would be produced by a previous conformational search. It most often is used with MINI to "polish" the results of a previous conformational search, using more stringent convergence criteria than were used in the search itself.

MULT must appear before MINI in the .com file.

arg1 Maximum number of conformers that can be saved

0      10000 (default)

n>0      n

Use as many CHIG commands as necessary to save all important chiralities.

CHIG commands must come after the READ command in the .com file. With MCMM searching, chirality will be checked after the Monte-Carlo step and also after the following energy minimization.

arg1-4 Atom numbers of chiral centers

arg1 First atom number for comparison

0      Compare all heavy atoms (atoms that are not hydrogens or lone pairs).

arg1 Maximum atomic separation (Å)

0      .05

1      .10

2      .20

n      0.1n

0      4.184 kJ/mol

<0      0 (All structure pairs will be compared geometrically, regardless of the energy difference between them.)

>0      This value, in Angstroms, is the maximum distance apart any two structures can be to be considered "the same structure" during conformational comparison. As before, despite the name of the command, the criterion used is the maximum (not RMS) distance between corresponding atoms following optimal rigid-body superposition.

<0      If arg6 is given a negative value, no conformational comparisons are done, and all conformational pairs are considered dissimilar

In applying the ATEQ commands, the program will generate all permutations of equivalenced atoms to try for a near perfect geometrical match (i.e. find a duplicate conformer). Such an approach will generate, inter alia, some nonsense permutations with clustered equivalent atoms (e.g. phenyl rings) but such permutations will never match and do not cause problems.

Turning on DEBG 81 causes full information to be printed.

arg1 Atom number of atom having other equivalent atoms

arg1 -4 Equivalent atom numbers

NSRO must come before READ or TRED commands and after COMP commands.

arg1 Rotation increment

NSRF - Numbering System ReFlection.

NSRF must come before READ or TRED commands.

NANT - Do NOT consider enantiomers to be duplicates

DEMX - Delta-E MaX energy windowing

A second energy window may be set in arg6 (suggested value 1.5-2 times that in arg5) which will be used to reject structures before complete minimization by a check of the relative energy at iteration number arg2. This allows the overall procedure to be speeded up by aborting the minimization of any structures having energies that appear too large partway through the minimization.

arg1 Identifier

arg2 Number of iterations before preliminary energy test

A reasonable value for arg2 is 1/3-1/2 of the number of iterations to give minimization convergence for a typical conformation, but it is wise to minimize several conformations of the actual structure to see how many iterations are necessary to bring the energy to within several kJ/mol of its final value.

arg5 Energy window for final test

arg6 Energy window for preliminary test

NORE - NO REordering done on output structures

NORE must come before READ or TRED commands.

Conformational Searching:

The output file from the search contains in the header lines of the individual structures the number of times each structure was found. Therefore, the full benefits of usage-directedness are obtained in a subsequently run search. This degeneracy information is ignored, for technical reasons, during a network-distributed search. In a distributed search, or in any search seeded from an output file produced by an earlier version of BatchMin, the structures are treated as if they each occurred exactly once in a previous search. Debug (DEBG) flag 360, if set, instructs the program to ignore the degeneracy information even if it would otherwise utilize it.

Searches may be updated during program execution. When a search is updated, the information in the temporary file (filename.tmp) is written to the output file, after discarding structures which are not within the specified energetic window of the current global minimum. A summary of the job progress thus far is also printed. This summary includes information about how many times various structures were found and about the convergence of these structures during minimization. As described in Chapter 3, Interacting with a Running BatchMin Job, updates can be triggered interactively by the user. Automatic, periodic updates can be controlled using the MCOP command.

For a discussion of conformational search protocols, see the MacroModel Primer. As discussed in the Primer, it is advisable to perform the search without exhaustive minimization of all found structures and to subsequently reminimize the surviving structures exhaustively.

This can now be done without initiating a new BatchMin job, by inserting into the .com file a RWND command following the MINI command that terminates the search setup, then inserting a BGIN/END loop within which a READ/MINI sequence is specified. The COMP atoms used in the search will continue to be active during the reminimization.

The maximum number of conformations that can be stored when using MCMM, LMCS, SPMC, or MULT is no longer limited to 10000. Please see the respective command descriptions and the section on Program Capacity for further details.

LMCS - Low-Mode Conformational Search

LMCS has been significantly altered since its introduction in Batchmin 6.0.A publication describing the algorithmic details of the new low-mode conformational search method will appear in the Journal of Computational Chemistry. The main new features are as follows:

1 LMCS no longer requires storage space for low-mode eigenvectors. Application of advanced, fast diagonalization algorithms now allow the calculation of low-mode eigenvectors on the fly.

2 Multiple LMCS steps are now allowed as an alternative to the original, single LMCS leap along a low-mode eigenvector. This facility comes in two flavors: LMCS-SHAKE and mode-following.

LMCS-SHAKE follows the original vector, but every two Ångstroms along it applies a few steps of steepest descent minimization to relieve any strain due to distorted bond lengths and bond angles introduced by the move.

The mode-following (eigenvector-following) option allows the user to apply the original low-mode search concept: "Since the potential energy hypersurface is a network of interconnected minima and saddle points, we reasoned that one could utilize a procedure that relies on eigenvector following for conformational searching. Thus, one could initiate the search by starting with any local minimum. By using one of the eigenvector-following techniques, one could locate a saddle point associated with this minimum and then the other minimum associated with this saddle point. By application of the eigenvector-following technique to the second minimum or to a different eigenvector of the first minimum, additional minima could be located which could then be used to find additional saddles, etc." (quoted from the JACS article cited above).

The mode-following option utilizes the same eigenvector-following saddle pointsearch method used in the SDLP command (see details there). If LMCS mode-following locates a saddle point, it proceeds as follows. The eigenvector associated with the negative eigenvalue is computed, followed by a short move along that eigenvector away from the starting structure. The resulting structure (slightly lower in energy than the saddle point structure) is then subjected to energy minimization to locate the minimum energy structure on the other side of the saddle point.

If, however, LMCS mode following cannot locate a saddle point, the procedure simply restores the starting (minimum) structure, which will be automatically "rejected by starting geometry". Thus, only minima found via saddle points will be stored. This makes LMCS mode-following useful for the mapping of conformational interconversions in a local region of the potential energy surface. The recommended procedure for this is to set LMCS arg5=-1 (each and every step mode-following), and MCSS arg1=0 (random walk structure selection) or LMCS arg4=1 (local search mode).

LMCS mode-following is not intended for general conformational searches. Simple LMCS or LMCS-SHAKE (LMCS arg5>=0) is much more efficient for this purpose. LMCS mode-following is only recommendedfor local searches exploring the conformational interconversions of a molecule. DEBG 920 saves all the intermediate structures during LMCS-SHAKE or mode-following in the .out file and colors them so that one can conveniently visualizethe different multiple LMCS moves.

3 LMCS can now be combined with MCMM search. Several tests have confirmed that the most efficient use of LMCS is to allow for explicit torsional rotation of key torsion bonds, especially in acyclic structures. Therefore, one can now freely combine LMCS with TORS commands (with RCA4 if necessary). Of course, MOLS commands can also be applied to translate/rotate independently movable molecules. See also MCOP command.

4 LMCS no longer requires a frequency limit for selecting the low-frequency modes. The user can simply specify the number of low-modes to be considered.

Reflecting the changes introduced in LMCS, the LMCS command arguments have been altered.

0      Carry out the search until arg2 structures have been found. We do not recommend the use of this default.

0      the maximum number of conformations that can be stored is the value specified in arg1 or 10000, whichever is greater.

>0      this is the maximum number of conformations to save during the search

0      Default: 10 (pure modes).

<0      LMCS will explore a random linear combination of the first |arg3| number of modes, rather than exploring single pure modes at a time.

0      Global search (each Monte Carlo step begins with the preceding Monte Carlo structure, providing the structure is within 100 kJ of the global minimum). This is equivalent to MCSS (arg1=0, arg2=0, arg4=100.0).

1      Local search (each Monte Carlo step begins with the original structure). Generally used with small coordinate variations in TORS or MOLS to find other minima which are closely related to the starting structure.

0      Default: Single LMCS leap (BatchMin 6.0 behavior).

>0      Frequency of using LMCS-SHAKE (must be in range 0 to 1).

<0      |arg5| is frequency of using mode-following (arg5 must be in range 0 to
-1).

0      Default: 0.25

>0      Other fraction.

It is often useful to perform a short conformational search with the default values of arg7 and arg8, and, based on the results, adjust these arguments accordingly. If many conformations minimize back to the starting conformation, increase arg7 (and perhaps arg8). If many conformations are ruled out because of distorted sp3 carbons, decrease arg8 (and perhaps arg7). The information needed to make these choices will become visible by specifying MCOP arg1=1.

0      Devault: 3 Å

>0      Other value to be used.

0      Default: 6 Å

>0      Other value to be used.

The TORS command is used to specify dihedral angles to be varied; the MOLS command specifies relative positions of multiple molecules, as in an enzyme-substrate docking procedure. In addition, RCA4 commands and LIGB commands can be used to open rings and break ligand bonds, respectively, before performing torsional or relative molecular motion. CHIG commands should be specified for ring-closure atoms as well as to retain chirality about other centers. TORC commands may be used to hold double-bond configurations constant.

The method is described in G. Chang, W.C. Guida and W.C. Still, J. Am. Chem. Soc., 111, 4379 (1989) and J. Am. Chem. Soc., 112, 1419 (1990).

Only unique structures will be retained, as in the MULT conformational searches. Use DEMX to set an energetic window to select low energy conformations. It is usually found that not all structures converge in minimization during a conformational search. A MULT minimization of the output file is recommended to achieve convergence for the final result.

While the default search method is random walk, we find that the usage-directed search (MCSS arg1=2) gives improved search performance.

arg1 Number of Monte Carlo steps to be carried out before stopping

0      Carry out the search until arg2 structures have been found. We do not recommend the use of this default.

0      The maximum number of conformations that can be stored is the value specified in arg1 or 10000, whichever is greater.

>0      this is the maximum number of conformations to save during the search

Greater control over this parameter may be obtained using the MCNV command; this is the most common procedure.

arg4 Search mode:

0      Global search (each Monte Carlo step begins with the preceding Monte Carlo structure, providing the structure is within 100 kJ of the global minimum). This is equivalent to MCSS (arg1=0, arg2=0, arg4=100.0).

1      Local search (each Monte Carlo step begins with the original structure). Generally used with small coordinate variations in TORS or MOLS to find other minima which are closely related to the starting structure.

SPMC - Systematic Pseudo Monte Carlo search.

It is suggested that torsional memory (MCSS arg3) be activated when using SPMC to prevent retracing of points in conformational space when starting from different starting geometries. If rings are being varied (i.e. RCA4 commands are being used), geometrical preoptimization (MCOP arg2) should also be activated.

Use with MCNV arg1=1 and arg2=N-1, where N is the number of variable torsions plus the number of molecules being independently translated/rotated with MOLS commands.

Details of the method: Jonathan Goodman and W. Clark Still, J. Comput. Chem., 12, 1110 (1991).

The arguments are the same as for MCMM, except arg3:

arg3 Maximum resolution for torsional alterations

MCOP - Monte Carlo options.

Despite its name, MCOP specifies parameters for use in low-mode (LMCS) as well as Monte-Carlo searches. Arguments 4 and 5 refer only to LMCS. Starting in MacroModel 6.5, these arguments have new meanings and arguments 6 and 7, which pertained to the earlier LMCS methodology, have been eliminated.

arg1 Number of steps between printout to log-file

0      Print to logfile every 250 Monte Carlo steps

1      Print to logfile every step.

n      Print to logfile every n steps.

0      Off.

1      On. Preoptimizes variable internal coordinates to improve ring closure distances. Recommended for SPMC of ring systems.

· The current .tmp file is removed, and structures that are to be saved (based on the value of the current global energetic minimim) are written to the output file.

· A summary of the progress of the search so far is written to the log file.

· If a <jobname>.upt file is created in the directory from which the job was initiated, this will cause an immediate update, in addition to those specified by arg3.

0      Default: Perform an update every tenth of a run, but not more often than every ten steps nor less often than every 500 steps.

n      Perform an update every n steps.

0      Not an LMCS serial job

¦0      LMCS serial job; this implies that a separate conformational search will be performed for each structure in the input file. This takes advantage of the ability of LMCS to define fruitful search directions without specification of variable torsions. An LMCS serial job can be run only when there are no commands specifying atom numbers - such as TORS or CHIG - which might translate to incorrect specifications in the different input structures.

0      If this is an LMCS job, all steps will be LMCS steps.

1      If this is an LMCS job and there are TORS or MOLS commands present, this fraction of moves will be TORS or MOLS (i.e., not LMCS) moves.

This command is active only when doing global searching (i.e., when MCMM or SPMC arg4 = 0). In any case, structures must be within 100 kJ of the current global minimum to be candidates for starting geometry selection.

arg1 Starting-structure selection criterion

0      Random walk. Most recent structure will be chosen whose energies are allowed by args2 and 5.

1      Use-directed. The least used structures will be used as starting geometries if their energies are allowed by args2 and 5. "Use" is defined as (times used as starting structure) - (times resulting structure is kept).

2      Use-directed. The least used structures will be used as starting geometries if their energies are allowed by args2 and 5. Use defined simply as as (times used as starting structure).

0      Arg5 will be used directly; recommended.

1      Arg5 will be multiplied by a random number between 0 and 1.

0      Torsional memory is not used.

>0      Torsional memory is used. Structures are considered identical if all torsions match within RES/arg3 where RES is the operative search resolution (smallest value = 2).

MCTS - Monte Carlo Torsion Selection.

Use in conjunction with MCMM to favor torsion angle selection near local torsional minima for the angles being varied. One MCTS command is required for each torsion which is to be effected. Arg1-4 are the atoms defining a particular torsion angle; i.e., arg2-3 should appear as a rotatable bond in a TORS command. Arg5-7 are 1-fold, 2-fold and 3-fold torsional barriers which are used to compute local torsional energies as part of the test for an allowable value of the randomly selected Monte-Carlo angular change. After a Monte-Carlo variation of a torsion angle described by arg1-4 of this command is performed, a local torsional energy (E_T) is computed based on the value of the dihedral angle, , using the usual MM2 formula:

E_T = (V₁/2)(1+cos ) + (V₂/2)(1-cos 2) + (V₃/2)(1+cos 3) - E_T,min

where E_T,min is the minimum possible value of E_T. If E_T is greater than 1, the torsion is rejected and a new random torsion angle is chosen. Otherwise, E_T is compared with a random number between 0 and 1 and, if E_T is larger than that number, a new random torsion angle is chosen. This scheme selects for local torsions which are low in energy. For sp3-sp3 linkages, one can favor the gauche and anti conformers (the minima) by using a V₁ (arg5) and V₃ (arg7)of 0.25. This will cause totally eclipsed (0-degree torsion) torsions to be strongly disfavored, 120-degree torsions to be moderately disfavored and the gauche and anti conformations to be favored. By choosing V₁-V₃ with care and using a random number for comparison, even high energy geometries are occasionally explored.

arg1-4 Atoms defining the torsion

Monte Carlo internal coordinate conformational search is performed with minimizations on a single structure. Variable internal coordinates are specified by TORS and/or MOLS.

MCSM can be used with cyclic structures providing that either ring bonds are not varied or that ring closure commands (RCA4) are used for each ring in which variable torsions are used. During the run, random variations will be applied to 2-4 randomly selected dihedral angles from the TORS lists or molecular translations/rotations from the MOLS lists for each Monte-Carlo step. If some other range of variable coordinates is desired, the range is set with the MCNV command.

If used within a BGIN/END loop, all structures in the input file will be read and the global minimum found will be listed to the output file at the end of every MC iteration set for each input structure. The ultimate global minimum would be found by examining the energies of each of the output structures.

Unlike MCMM, this command (MCSM) requires no MINI command. It must appear after a READ command.

In general, Monte Carlo searches should use CHIG commands to maintain all chiral centers and TORC commands to hold double bond geometries constant. If chirality or olefin geometry is lost in any step, then following steps will be wrong if the resulting geometry is used for subsequent steps.

arg1 Minimization mode

0      steepest descent

1      PR conjugate gradient (best general method).

3      Variable Metric (not recommended with MCSM).

4      Full matrix NR (not recommended with MCSM).

9      TNCG (good for flexible structures).

0      No linesearching (best choice).

1      Linesearching on.

0.0      Metropolis sampling will not be done; every structure will be used as the next starting point

0.0      Continuous sampling at the arg5 temperature will be done throughout the run. If a nonzero temperature is supplied, cooling from the arg5 to the arg6 temperature will be carried out during the run. This slow cooling is equivalent to simulated annealing.

As in MINI arg5.

As in MINI arg6.

For MCMM on single unsymmetrical molecules, we find it best to specify the range as 1 to N, where N is the number of variable dihedral angles, when TORS commands are being used. It is best to use a range of values, rather than a single value. When MOLS is being used, N should be incremented by one. When ZMAT is being used, N should take account of all degrees of freedom.

Used with MCMM, MCSD, MCLO, IMPS and SPMC commands.

In the context of MC or MC(JBW) simulations this command sets the number of degrees of freedom to be changed at each MC step or randomized at each MC(JBW) step. A degree of freedom is either a bond length, bond angle or torsion or a molecular translation or rotation along or about a single axis. This number should be set in such a way to provide a compromise between acceptance rate and conformational interconversions. When args 1 and 2 of this command differ, MCNV defines a range for the number of degrees of freedom to be changed at each step. When the two arguments are identical, MCNV defines an exact number for the degrees of freedom to be changed at each step. In both cases, the initial values will be modified during the run by the adaptive mechanism unless debug 103 is defined.

For MC, MC(JBW) or MCSD simulations, a number of degrees of freedom must be defined and consequently, the MCNV command should be present; however, its two arguments can be 0, in which case the program will provide a default range, from 1 to maximum number of the degrees of freedom of the molecules. Such a range is probably not efficient. For MC(JBW)/SD, no randomization in the JBW part is needed and all the randomization can effectively be done by the SD part of the simulation. Doing so will increase the number of conformational interconversions. In order to achieve that, the MCNV command should be omitted and arg 2 of the MCSD command should be set to a negative number.

arg1 Minimum number of degrees of freedom altered

0      Default: 1

0      Default: number of variable degrees of freedom in the system.

0      Do not cluster torsions; recommended.

1      All torsions rotated will be in a contiguous group as defined by the ordering of torsions in the TORS commands.

2      Allow a single intervening unused torsion.

n      If, at a given stage, m torsions are rotated, these will be selected from a contiguous group of (m+n-1) torsions selected from the list taken from the TORS commands.

arg1 Seed value

TORS - variable TORSion selection

Variable torsions within rings require the ring-closure commands RCA4 in addition to TORS commands. It is advisable to specify at least two variable torsions within each ring containing RCA4 ring closures. The atoms of a ring closures (args 2 and 3 in RCA4) must not be listed as variable torsions.

The minimum and maximum angular increment (arg5 and arg6) refer to the torsions given in arg1-4. It is possible to use a different angular increment for each torsion by using only arg1, arg2, arg5 and arg6 and a different TORS command for each torsion. For global searching, arg5 and arg6 of 0.0° and 180.0° are appropriate values. If you wish to focus the search on conformations having only small angular variations from the starting conformation, a value of 30.0° for arg6 could be used.

If you are searching multicyclic ring systems, you should include CHIG commands for any substituted atoms at the ring closure atoms (arg2 and arg3 in RCA4) to assure maintenance of stereochemistry.

When doing substructure MC searching, always order the pairs of atoms defining torsions such that the second atom of each pair is not connected to any fixed atoms (FXAT) except via first atom (in the torsional movements, the chain connected to the second atom is the one which will actually be moved). If both ends are anchored by FXAT commands, then a ring closure (RCA4) command will be necessary. TORS and MOLS commands can be used together.

arg1-2 Atom numbers specifying first torsion

arg6 Maximum dihedral angle variation

TRES - Torsional RESolution.

arg1-2 Atoms defining the torsional angle

arg3 Resolution for this angle

MOLS - Variable MOLeculeS selection

MOLS commands must come after TORS commands.

During a search, random molecules are selected for motion. For each molecule, rotation about all three axes and tranlation along all three axes are performed by amounts selected randomly from within the ranges specified in arg5-6 and arg7-8. MOLS has the same relationship to LIGB as TORS has to RCA4: the bonds specified in a LIGB command are broken before the MOLS-specified molecular motion is carried out, then the LIGB bonds are remade prior to minimization of the resulting structure.

During a long enough search, if pair-list cutoffs are in effect, as is normal (see EXNB), one molecule will eventually wander far enough away from another that no nonbonded energies between them exist anymore. In this situation, further searching just explores random spatial dispositions of this pair with no energetic contribution from their mutual interaction. Unless already-found binding conformations are lower in energy by at least the DEMX-specified energy, this will lead to essentially an infinite and fruitless search of conformational space. To avoid this, use FXDI to contrain the distance between atom pairs spanning pairs of molecules to some maximum distance. This maximum distance should be specified as the half-width of an FXDI potential. In practice, we do this only if we encounter difficulties without doing so.

arg1-4 Atom in a molecule to be moved

<0      Perform rotations about the atom number given.

>0      Perform rotations about the center of mass of the molecule containing the atom.

arg6 Maximum rotational variation

arg7 Minimum translational variation

arg8 Maximum translational variation

LIGB - LIGand Bonds

This command defines bonds to be broken, creating molecular fragments which will be moved independently during the search. A MOLS command must be present for each fragment to be moved. For a bidentate ligand, there will be two LIGB bonds specified for the single MOLS command that moves the ligand; for a tridentate ligand, there will be three, and so on.

This procedure allows an MCMM search to find, for example, both mer and fac isomers of an octahedral complex with stoichiometry MA₃B₃. LIGB can also be used to extend a conformational search to a configurational search; for example, by specifying bonds to chiral carbons as LIGB bonds, the R and S configurations about these carbons will be explored.

arg1: First atom in bond to be broken (typically a metal atom)

0      Add all bonds to arg1 to the LIGB list.

>0      Add the arg1-arg2 bond to the LIGB list for arg1.

<0      Remove the bond between arg1 and |arg2| from the LIGB list for arg1, if such a list already exists, or, if no such lists exists, create one with all bonds to arg1 on it except this one.

With MCMM and MCSM and for small-medium rings, arg5 and arg6 should be approximately 0.5 and 2.5. For large rings, arg5 and arg6 should be ca 0.1 and 5.0.

With SPMC and for small-medium rings, arg5 and arg6 should be approximately 1.0 and 2.0. For larger rings, arg5 and arg6 should be ca 0.5 and 3.0-4.0. The exact choice is not very important but has a minor effect on search efficiency.

It is forbidden that an arg2 or arg3 atom be used in more than one RCA4 command (common ring closure atoms are not allowed). The closure angle arguments (arg7 and arg8) are optional and refer to both closure angles 1-2-3 and 2-3-4. Our tests so far indicate that there is little reason to use arg7 and arg8 closure angle constraints.

arg1-4 Atom numbers within ring

arg5 Minimum allowable ring closure dist (Å) (default: 0)

arg7 Minimum allowable closure angle (deg) (default = 0.0)

DISC - DIStance Constraint.

arg1-2 Atom numbers defining distance

0      Check distance before minimization.

1      Check distance after minimization.

arg1-4 Atom numbers specifying a dihedral angle

arg1 Maximum number of constraint failures with constant torsion set (default: 10000)

arg1 Sampling interval

0      Write the last structure sampled and the global mimimum; the latter appears last in the output file.

n      Write every n'th structure sampled.