Conformational Search Panel

The Conformational Search panel is used to set up a conformational search starting from the structure in the Workspace or from selected entries in the Project Table.

To open this panel, do one of the following:

  • Click the Tasks button and browse to Structure Analysis → Advanced Search
  • Click the Tasks button and browse to General Modeling → Advanced Search
  • Click the Tasks button and browse to MacroModel → Conformational Search
  • Click the Tasks button and browse to Materials → Classical Mechanics → Molecular Mechanics → Conformational Search
  • Using
  • Features
  • Additional Resources

Using the Conformational Search Panel

The CSearch tab contains the controls that are directly related to conformational searches.

Before you start a conformational search, the values for certain variables need to be set, such as which torsions are to be rotated and which rings are to be opened. There are three ways to set up conformational search variables from the CSearch tab: using Perform Automatic Setup, using Perform automatic setup during calculation, or setting variables manually. The automatic setup procedures select comparison atoms and other conformational search parameters for you. For MCMM and mixed MCMM/LMOD calculations, comparison atoms, chiral atoms, torsion checks, molecule moves, variable torsions, and ring closures are automatically set up. For low-mode and large-scale low-mode calculations, comparison atoms, chiral atoms, and torsion checks are automatically set up.

Before starting a conformational search, variables must be set that determine which torsions are to be rotated, which rings are to be opened, etc. You can either set these variable automatically or manually:

  • To automatically generate all the necessary variables for the search, click Perform Automatic Setup.
  • To set the variables manually, choose an item from the Search variables option menu, then click the Edit button, to open the panel in which you can define and edit the conformational search variables. These panels are described in separate help topics. See the related topics list below.

If you choose to set the variables automatically, you can always review and edit the variables by using the Search variables option menu and Edit button.

Note: Automatic setup should not be used with constraints. If you set constraints and use automatic setup, MacroModel can fail because the automatic setup can request movement of atoms that have constraints.

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see bmin Command Help or macromodel Command Help. For information on the command file keywords, see the MacroModel Command Reference Manual.

Conformational Search Panel Features

Use structures from option menu

Choose the structure source for the conformational search.

  • Project Table (selected entries)—Use the entries that are currently selected in the Project Table.
  • Workspace (included entries)—Use the entries that are currently included in the Workspace, treated as separate structures.

Tabs

  • Potential
  • Constraints
  • Substructure
  • Mini
  • CSearch

Potential Tab Features

The Potential tab allows you to set parameters for energy calculations. The settings that define the force field and solvent treatment are the most critical for MacroModel energy calculations. The remaining options allow you to specify parameters for nonbonded interactions. Default settings for these parameters are automatically assigned using data from other settings within the program, or using sensible default values. Advanced users may wish to change these values.

Force field option menu

Choose the force field for the current task. The choices are MM2*, MM3*, AMBER*, OPLS, AMBER94, MMFF, MMFFs, OPLS_2005, and OPLS4. The default is OPLS4 if it is available, otherwise it is OPLS_2005, unless you set the default in the Force Field settings section of the Preferences Panel.

Use customized version option

Use your customized version of the OPLS4 force field, rather than the standard version in the distribution. Only available when you choose OPLS4 from the Force field option menu and you have the appropriate license. This option is set by default to the value of the Use custom parameters by default option in the Preferences panel, under Jobs - Force field, when the current panel is opened. The default directory for the customized version can also be specified as a preference, in the same location.

If the customized version is missing or invalid, the text of this option turns orange and an orange warning icon is displayed to the right, with a tooltip about the problem.

Parameter set button

Select the set of custom parameters for the OPLS4 force field. Opens the Set Custom Parameters Location Dialog Box. Only available when you choose OPLS4 from the Force field option menu and you have the appropriate license.

Restrain bonds to metals around input geometry option

Add a harmonic restraint to restrain bonds to metals around the input geometry. This option is useful when the force field does not have good coverage of the metal-ligand bonds in the input structure. The atom restraints are sufficient to allow some movement of the coordinated atoms to relieve strain. The option is on by default; deselect it to allow the minimized geometry of the coordinated atoms to be determined by the force field.

Solvent option menu

Choose an appropriate solvation treatment:

  • None: simulates an isolated system in a vacuum
  • Water (the default)
  • CHCl3
  • Octanol

The solvent effects are simulated using the analytical Generalized-Born/Surface-Area (GB/SA) model. For all calculations using the GB/SA solvation model, the constant dielectric treatment is automatically used for the electrostatic part of the calculation. When you choose a solvent, the dielectric constant is defined by the solvent, so the Electrostatic treatment option menu and Dielectric constant option menus are not available.

Electrostatic treatment option menu

Choose a method for calculating the electrostatic terms within the force field:

  • Constant dielectric: electrostatic terms are evaluated using an expression of the form:

    q1 q2 / ε r

    where q1 and q2 are the partial atomic charges, r is the interatomic distance, and ε is the dielectric constant of the medium (usually 1.0). This is set when a solvent is chosen.

  • Distance-dependent: electrostatic terms are evaluated using an expression of the form:

    q1 q2 / εr2

  • Force-field defined: automatically selects the appropriate treatment (Constant dielectric or Distance-dependent) that is compatible with the chosen force field.

This option menu is not available when a solvent is selected, because the use of the solvent requires a constant dielectric whose value is defined by the solvent. The MMFF and MMFFs force fields use a “buffered” constant dielectric treatment; see Halgren [10,11].

Dielectric constant text box

Specify the value of the dielectric constant directly (ε in the above expressions). This value is usually 1.0 for vacuum and GB/SA solvation simulations. If Distance dependent has been selected as the electrostatic treatment, the dielectric constant value is used as a multiplying factor for the distance-dependent dielectric. So to set the electrostatic treatment to the occasionally used ε = 4r treatment, select Distance dependent and enter 4.0 in the Dielectric constant text box.

This text box is not available when a solvent is selected, because the dielectric constant is defined by the solvent.

Charges from option menu

Choose whether the charges used in the electrostatic portion of an energy calculation are assigned by the force field or obtained from the structure. The default is Force field. Regardless of the source, however, charges are written to the structure file when a job is started.

Cutoff option menu and text boxes

Choose a cutoff type and specify the cutoffs for nonbonded interactions (values are in angstroms):

  • Normal: sets the following cutoffs:
    Van der Waals7.0
    Electrostatic12.0
    H-bond4.0
  • Extended: sets the following cutoffs:
    Van der Waals8.0
    Electrostatic20.0
    H-bond4.0
  • None: all nonbonded interactions are considered.
  • User-defined: enter your own cutoff values for Van der Waals, Electrostatic, and H-Bond.

Cutoffs are characteristic distances, beyond which the interaction of atom pairs is not considered. Because distance dependencies of various nonbonded terms differ, a cutoff for each type of nonbonded interaction is considered. The van der Waals and electrostatic cutoff distances are the center of a soft cutoff that starts at 1 Å smaller than the specified distance and ends at 1 Å larger than the specified distance. Defining cutoffs speeds up calculations and reduces the amount of storage space required for calculations on large systems.

In most cases, the use of cutoffs can be justified because interaction between two nonbonded atoms becomes very small at large separation distances and need not be included in an evaluation of nonbonded energies. However, it must be realized that calculations in which cutoffs are used are approximations. If cutoff distances are set too small, the minimized structures and dynamics trajectories obtained may contain artifacts arising from the neglect of otherwise significant nonbonded interactions.

Note: The above warnings about insufficiently large cutoff distances should be considered before defining cutoffs that are shorter than those defined by the Normal option. Only in exceptional circumstances could this be justified.

Debugging options text box

Add the DEBG opcodes for the listed DEBG opcode numbers at the beginning of the MacroModel command (.com) file. The list can be separated by either commas or spaces.DEBG opcodes are a collection of debugging and miscellaneous settings.

Read Potential Settings From Command File button

Click to import potential energy settings from a Macromodel command file. You can use this option any time you want to run a job with the same potential energy settings you used in a previous job. Setting up MacroModel calculations in this way is helpful because you can easily reproduce your potential energy settings for multiple calculations.

Constraints Tab Features

The controls in the Constraints tab allow specification of atoms whose movement is restricted or forbidden during MacroModel calculations. Constraints are additions of energy penalty functions to the normal force field terms, which are usually flat-bottomed harmonic functions.

This tab contains four subtabs that you can use to define the different kinds of constraints. Each tab contains a table that lists the constraints and a set of picking tools that you can use to define a constraint. The force constant and the width of the flat bottom (if required) can be set by editing the table cells. To set the same force constant for multiple constraints, select the constraints, edit the value for one of them and press Ctrl+Enter (⌘Enter).

Specifying a nondefault force constant and half width prior to selecting atoms: If atom-centered constraints are being applied, constraint parameters can be set up beforehand with the Maestro command constrainedset. For example, to set the force constant to 50 and the width to 0.8, enter the following command in the Commands text box of the main window:

constrainedset constant=50 width=0.8

Constrained atoms that are subsequently selected use these constraint parameters.

Atoms tab

In this tab you can constrain individual atoms. The total number of atom constraints defined is shown in the tab label.

To constrain an atom, select Pick in the Define constrained atoms section, and click on the atom that you wish to constrain. A row is added to the table with the default force constant, and you can edit the table cells to change the force constant and set a range of free movement before the constraint is applied.

Constrained atoms table

This table lists the defined constraints. Multiple rows can be selected in the table with the usual shift-click and control-click. You can change the value in all selected rows for a given column by editing one of the values and pressing Ctrl+Enter (⌘Enter). The table columns are described below.

Atom Atom number of the constrained atom.
Frozen Checkbox for freezing the atom rather than constraining it. When the box is checked, the Force Constant and +/- columns are cleared; when the box is cleared, the previous values are restored. You can freeze multiple atoms by selecting the rows and checking the box in one of them.
Frozen atoms are those that do not have any forces acting on them during minimization or dynamics procedures, and hence will not move. Frozen atoms do, however, exert a presence on other, non-frozen, atoms through normal nonbonded interactions.
Force Constant Force constant for the constraint. The default value for the force constant is 100 kJ/mol Å2 for the OPLS_2005 and OPLS4 force fields, and 100 kcal/mol Å2 for all other force fields. You can edit the table cell to change the force constant. To change the force constant for multiple atoms, select the table rows, edit one of the values, and press Ctrl+Enter (⌘Enter).
+/- Width of the flat-bottomed region, in angstroms. This is the distance that the atom can move freely from its input position. The default value is 0, meaning that the constraint potential is in effect for all deviations from the input position.
Delete and Delete All buttons

Delete constraints. Delete deletes the constraints that are selected in the table, and Delete All deletes all constraints in the table.

Define constrained atoms picking tools

Select the atoms to be constrained using the standard picking tools. A constraint is added for each atom that is picked. If Markers is selected, the atoms to be constrained are marked with an orange cross and a "spring" icon in the Workspace display. The markers for the currently selected constrained atoms are colored turquoise. A padlock icon is added to the marker if the atom is frozen.

Distances tab

In this tab you can constrain distances between atoms. The total number of distance constraints defined is shown in the tab label.

To constrain a distance, select Pick in the Define constrained distances section, and click on the two atoms that define the distance you wish to constrain. A row is added to the table with the default force constant and current distance, and you can edit the table cells to change the force constant, set a target distance, and set a range of free movement before the constraint is applied.

Constrained distances table

This table lists the defined constraints. Multiple rows can be selected in the table with the usual shift-click and control-click. You can change the value in all selected rows for a given column by editing one of the values and pressing Ctrl+Enter (⌘Enter). The table columns are described below.

Atoms Atom numbers of the atoms that define the constrained distance.
Force Constant Force constant for the constraint. The default value for the force constant is 100 kJ/mol Å2. You can edit the table cell to change the force constant. To change the force constant for multiple distances, select the table rows, edit one of the values, and press Ctrl+Enter (⌘Enter).
Distance Target value for the distance, in angstroms. The default is the input value, but you can change it to force the distance to the new value.
+/- Width of the flat-bottomed region, in angstroms. This is the amount that the distance can change from the target value before the constraint is applied. The default value is 0, meaning that the constraint potential is in effect for all deviations from the target value.
Delete and Delete All buttons

Delete constraints. Delete deletes the constraints that are selected in the table, and Delete All deletes all constraints in the table.

Define constrained distances picking tools

Select the atoms to be constrained using the standard picking tools. A constraint is added for each atom that is picked. If Markers is selected, the distances to be constrained are marked in the Workspace with a purple dotted line. The markers for the currently selected constrained distances are colored turquoise.

Add All Atom Pairs button

Add all atom pairs in the Workspace selection to the table, or if there is no selection, add all atom pairs in the Workspace structure.

Angles tab

In this tab you can constrain angles between atoms. The total number of angle constraints defined is shown in the tab label.

To constrain an angle, select Pick in the Define constrained angles section, and click on the three atoms that define the angle you wish to constrain. The atoms are makred with a purple box as you pick them. On the third pick, the boxes are removed and a row is added to the table with the default force constant and current angle. You can edit the table cells to change the force constant, set a target angle, and set a range of free movement before the constraint is applied.

Constrained angles table

This table lists the defined constraints. Multiple rows can be selected in the table with the usual shift-click and control-click. You can change the value in all selected rows for a given column by editing one of the values and pressing Ctrl+Enter (⌘Enter). The table columns are described below.

Atoms Atom numbers of the atoms that define the constrained angle.
Force Constant Force constant for the constraint. The default value for the force constant is 100 kJ/mol rad2. You can edit the table cell to change the force constant. To change the force constant for multiple angles, select the table rows, edit one of the values, and press Ctrl+Enter (⌘Enter).
Angle Target value for the angle, in angstroms. The default is the input value, but you can change it to force the angle to the new value.
+/- Width of the flat-bottomed region, in degrees. This is the amount that the angle can change from the target value before the constraint is applied. The default value is 0, meaning that the constraint potential is in effect for all deviations from the target value.
Delete and Delete All buttons

Delete constraints. Delete deletes the constraints that are selected in the table, and Delete All deletes all constraints in the table.

Define constrained angles picking tools

Select the atoms defining the angle to be constrained using the standard picking tools. A constraint is added for each atom that is picked. If Markers is selected, the angles to be constrained are marked in the Workspace in green with a "spring" icon. The markers for the currently selected constrained angles are colored turquoise.

Add All Bond Angles button

Add all bond angles in the Workspace selection to the table, or if there is no selection, add all bond angles in the Workspace structure.

Torsions tab

In this tab you can constrain torsions between atoms. The total number of torsion constraints defined is shown in the tab label.

To constrain an torsion, select Pick in the Define constrained torsions section, and click on the four atoms that define the torsion you wish to constrain. The atoms are makred with a purple box as you pick them. On the fourth pick, the boxes are removed and a row is added to the table with the default force constant and current torsion. You can edit the table cells to change the force constant, set a target torsion, and set a range of free movement before the constraint is applied.

Constrained torsions table

This table lists the defined constraints. Multiple rows can be selected in the table with the usual shift-click and control-click. You can change the value in all selected rows for a given column by editing one of the values and pressing Ctrl+Enter (⌘Enter). The table columns are described below.

Atoms Atom numbers of the atoms that define the constrained torsion.
Force Constant Force constant for the constraint. The default value for the force constant is 1000 kJ/mol. (The units and default value are different from those for angles because the constraining function is a cosine rather than a quadratic function of the coordinate). You can edit the table cell to change the force constant. To change the force constant for multiple torsions, select the table rows, edit one of the values, and press Ctrl+Enter (⌘Enter).
Torsion Target value for the torsion, in angstroms. The default is the input value, but you can change it to force the torsion to the new value.
+/- Width of the flat-bottomed region, in degrees. This is the amount that the torsion can change from the target value before the constraint is applied. The default value is 0, meaning that the constraint potential is in effect for all deviations from the target value.
Delete and Delete All buttons

Delete constraints. Delete deletes the constraints that are selected in the table, and Delete All deletes all constraints in the table.

Define constrained torsions picking tools

Select the atoms defining the torsion to be constrained using the standard picking tools. A constraint is added for each atom that is picked. If Markers is selected, the torsions to be constrained are marked in the Workspace in green with a "spring" icon. The markers for the currently selected constrained torsions are colored turquoise.

Add All Torsions button

Add all bond torsions in the Workspace selection to the table, or if there is no selection, add all bond torsions in the Workspace structure.

Action buttons

These buttons can be used to perform actions on all the constraints.

Delete All Constraints button

Delete all constraints from all tabs.

Read .sbc File button

Read constraints from a substructure (.sbc) file. Opens a file selector, in which you can navigate to and select the file.

Write .sbc File button

Write all constraints to a substructure (.sbc) file. Opens a file selector, in which you can navigate to a location and name the file.

Substructure Tab Features

The Substructure tab allows you to define a substructure of freely moving atoms and any "shells" of constrained or frozen atoms that surround it.

In calculations involving large systems of atoms often only a portion of the system needs to be fully modeled. For instance, often it is sufficient to model only the immediate environment around the active site of a receptor-ligand complex. The substructure facility provides an effective mechanism for focusing the calculation on the key portions of such systems.

Substructure atoms are those atoms that are modeled in the normal manner, that is they move freely and interact with other atoms. To provide an effective environment for the substructure atoms, you can define shells of restrained or even immobile (frozen) atoms. These shells can be specified in a number of ways. A common method is to select those atoms that lie within a given distance from substructure atoms or from those atoms in previously defined shells. A typical setup consists of a shell of constrained atoms (radius 5-8 Å) around the substructure and then a shell of frozen atoms (radius 5-8 Å) around the first shell. If substructures and shells are used in this way, any atoms that are not either in the substructure or in the shells are completely ignored in a substructure calculation. By ignoring such atoms and calculating only certain types of interactions amongst the shell atoms, you can dramatically reduce the required memory and computing time.

Note: If only shell atoms are defined and no substructure atoms are defined, all unspecified atoms are treated as substructure atoms and thus fully modeled.

It is possible to read in an existing substructure definition file and display the resulting substructure in this panel. However, note that substructure files only store the numbers of the atoms in the substructure or shells (with the restraining force constant), not the rules used to identify to which shell they belong. In any particular shell, atoms are just listed in Additional atoms for shell with a shell radius of 0, even if the shells were originally defined using distances. However, if substructure definition files are written in ASL format, the ASL syntax for the shell is stored.

Substructure Definition Section

Note: If no substructure atoms are defined, all unspecified atoms that are not in shells are treated as substructure atoms and thus fully modeled.

Freely moving atoms (substructure) picking controls

Use the standard picking controls to define the freely moving atoms for the substructure. Normal energy calculations can be performed on the substructure atoms.

Expand to atoms within radius of text box

Specify a radius for expanding the substructure. The substructure includes all atoms within the specified radius of the atom set defined in Atoms for substructure.

Complete residues option

Select to expand the substructure to include residue boundaries, thereby ensuring that only complete residues are included in the substructure. This substructure is often used when modeling biopolymers.

Calculate constrained-atom mutual interactions option

Select this option to calculate mutual interactions between constrained atoms (both fixed and frozen) and include them in the total energy. By default, these terms are not included in the total energy, which affects energy comparisons.

Shell Definition Section

Once the substructure has been defined, it is normal to define "shells" of atoms around the substructure that are to be constrained or frozen. To define a new shell around the substructure, click New below the Shells list, then select the atoms in the Selected shell section.

Shells (constrained and frozen atoms) list

Lists the defined shells, numbered sequentially. To add a shell, click New below the list, and use the controls in the Selected shell section to specify the shell. When you select a shell in the list, the shell definition is displayed using the controls in the Selected shell section.

New button

Click to create a new shell. The shell appears in the Shells list. You can then use the controls in the Selected shell section to select atoms in the shell.

Delete button

Delete the shell that is selected in the Shells list.

Radius

Specify a radius for the currently selected shell. All atoms within this distance from atoms in the substructure or in lower-numbered shells are selected.

Complete residues

Click to automatically include complete residues in the selected shell. In biopolymers, a common practice is to select shell boundaries so that they coincide with complete residues.

Force constant

Specify a force constant, if the atoms in the selected shell are to be constrained with harmonic positional constraints.

Freeze atoms

Click to freeze, rather than constrain, the atoms in the selected shell. Frozen atoms have no forces acting on them during minimization and dynamics procedures (and hence do not move from their starting positions), however, they do interact with other (moving) atoms

Additional atoms for shell

Use the standard picking controls to define atoms to add to the currently selected shell. Atoms may be added even if a substructure has not been defined.

Input and Output Section

In this section you can read and write substructure files, which include the substructure and the shell definitions.

Read .sbc File button

Click to import substructure and shell definitions from an existing .sbc file. Opens a file selector so that you can navigate to and select the file.

Write .sbc File button

Click to save substructure and shell definitions for future use. Enter the desired filename for the .sbc file in the dialog box that opens

Write ASL formatted .sbc file option

Select this option to write substructures in ASL format (with ASL1 and ASL2 opcodes) to the .sbc file. For more information on use of ASL in substructure files, see Constrained Energy Minimization Opcodes.

Write absolute atom coordinates option

Select this option to write the absolute atom coordinates to the .sbc file. By default, zeroes are written, meaning that the coordinates from the structure are used for the constraints rather than the coordinates in the .sbc file.

Atom Count

Below the input and output section is a count of the number of substructure atoms, the number of fixed atoms, and the number of frozen atoms. This count is updated when you add atoms to the substructure or shells.

Mini Tab Features

The Mini tab allows you to choose the minimization method and set convergence parameters. This tab is present in all MacroModel panels that perform minimization as part of the task.

Method option menu

Select a minimization method:

PRCG (Polak-Ribier Conjugate Gradient):

This is a conjugate gradient minimization scheme that uses the Polak-Ribiere first derivative method [25] with restarts every 3N iterations. This is the best general method for energy minimization, but it should not be used to find transition states. The code for this method is highly vectorized for efficient operation on vector hardware.

TNCG (Truncated Newton Conjugate Gradient):

TNCG [27] uses second derivatives and line searching, and is highly efficient for producing very low gradient structures. It generally converges in one tenth the number of iterations necessary for a PRCG, but each iteration takes more time. Often FMNR re-minimization of TNCG structures gives the lowest final gradients.

OSVM (Oren-Spedicato Variable Metric):

This is a variable metric minimization that uses the Oren-Spedicato modification [26] of the Fletcher-Powell quasi-Newton method. Convergence to saddle points is possible. Typical convergence occurs in 3N - 6N iterations but note that iteration speed is relatively slow. OSVM is not recommended for structures with poor starting geometries.

SD (Steepest Descent):

This is a steepest descent minimization method. SD should not be used to find saddle points, and convergence is poor towards the end of minimization. This is a good method for starting geometries that are far from the minimum, but a switch to another method is recommended when derivatives fall below 10 kJ/A or so. SD is one of the least efficient methods. PRCG is usually a better choice.

FMNR (Full Matrix Newton Raphson):

With this method, convergence to saddle points is not uncommon. Use FMNR with preminimized structures having RMS gradients of less than 0.1 kJ/mol. Use line searching (select after prompt) for problematic cases, or if the RMS First Derivative is greater than 0.1. The preminimization requirement derives from the Newton Raphson assumption of a quadratic potential surface. The method works only if the assumption is valid. FMNR is the most effective method for fully converging structures, but it requires significant computational resources for large structures.

If you wish to find saddle point structures, you must start very close to the saddle point, and disable line searching.

FMNR has excellent convergence properties, and typically converges in 2-10 iterations.

LBFGS (Low-memory Broyden-Fletcher- Goldfarb-Shanno ):

A method that performs well with large structures.

Optimal

This option selects a method that should be optimal for the calculation type. It uses the TNCG method if the number of unfixed atoms is less than 1000 and solvation is employed; otherwise it uses the PRCG method with 3-point line searcher. (Sets MINI arg1 to 20).

Maximum iterations text box

Specify the maximum number of iterations to be performed. If the minimization has not converged by this point, it will be terminated. The default for most of the minimization methods is 500 iterations, but for SD and FMNR, the default is 50 iterations.

Note: In the Ligand Torsion Search panel, this option contains two additional parameters:

  • Pre-minimization of input structures
  • Post-minimization of generated structures (the default is 50, which is the recommended maximum)
Converge on option menu

Choose a convergence criterion:

  • Gradient: the RMS gradient of the energy with respect to the coordinates, in kJ mol-1 Å-1 (default)
  • Energy: the energy difference between iterations in kJ/mol
  • Movement: RMS change in atom positions at each iteration, in angstroms.
  • Nothing: the minimization attempts to run for the maximum number of iterations as described above.
Convergence threshold text box

Specify the threshold to be applied to the Converge On method. The default is 0.05.

CSearch Tab Features

Customize the search section

Method option menu

This option menu allows you to choose one of six methods for performing a conformational search. MCMM and SPMC are Monte Carlo methods that require a number of variables to be defined (see Search variable section). For pure low-mode conformational searches, setting these variables is optional. The choice of method determines what options are available in this tab.

  • Torsional sampling (MCMM)

    This is the recommended conformational search method. The input structure is modified by random changes in torsion angles and/or molecular position as specified in the panels opened by the Torsion Rotations or Molecule Trans/Rot buttons. Ordinarily, whether a single structure or multiple structures appear in the input file, they will first be read in, minimized, and treated as if already found by the MCMM procedure. This allows a new search to be initialized from the output of a previous search, by using the output file of the old search as input for the new one. See MacroModel Conformational Search Methods, and the MCMM opcode description in the MacroModel Command Reference Manual — Contents, for a detailed description of this method.

    Serial torsional sampling (MCMM) is an automated procedure for performing a separate MCMM search on each structure in the input structure file, and is enabled by selecting Multi-ligand. For this procedure, Perform automatic setup during calculation is selected and cannot be deselected.

  • Systematic torsional sampling (SPMC)

    This method is similar to MCMM, but uses a systematic search instead of a random search. The search begins at low torsional resolution (120°), searches all angles without duplicating coverage, then doubles the resolution. This method has the advantage of not retracing its path and consequently converges the final stages of the conformational search more efficiently than MCMM. Like MCMM, the method is effectively open-ended: it will search conformational space until you stop it. See MacroModel Conformational Search Methods, and the SPMC opcode command description in the MacroModel Command Reference Manual — Contents, for a detailed description of this method.

  • Low-mode sampling

    This method, termed LMOD, is highly efficient and has the advantage that ring structures and variable torsion angles do not need to be specified. This conformational search method works by exploring the low-frequency eigenvectors of the system, which are expected to follow “soft” degrees of freedom, such as torsions. LMOD methods search conformational space aggressively enough to switch the chirality of atoms within the structures provided. Chirality checking should be used for chiral atoms for which such chirality switching is undesirable. See MacroModel Conformational Search Methods, and the LMCS opcode description in the MacroModel Command Reference Manual — Contents, for a detailed description of this method.

    Serial low-mode sampling is an automated procedure for performing a separate low-mode search on each structure in the input structure file, and is enabled by selecting Multi-ligand. For this procedure, Perform automatic setup during calculation is selected and cannot be deselected.

  • Mixed torsional/Low-mode sampling

    This method uses a combination of the random changes in torsion angles and/or molecular position from the MCMM method, together with the low-mode steps from the LMOD method used in pure low-mode. See Mixed MCMM/Low-Mode Conformational Search Methods, and the MCMM and LMCS opcode descriptions in the MacroModel Command Reference Manual — Contents, for a detailed description of this method.

    You can use this method to perform a separate search on each structure in the input structure file by selecting Multi-ligand, next to the Method option menu. For this procedure, Perform automatic setup during calculation is selected and cannot be deselected.

  • Large scale low-mode sampling

    Large Scale Low-Mode (LLMOD) is similar to Low-Mode (LMOD), except that it uses techniques to reduce the memory requirements so that it can be applied to much larger systems such as protein-ligand complexes. Like LMOD, LLMOD methods search conformational space aggressively enough to switch the chirality of atoms within the structures provided. Chirality checking should be used for chiral atoms for which such chirality switching is undesirable. See the LMC2 and ARPK opcode descriptions in the MacroModel Command Reference Manual — Contents for a detailed description of this method.

    Large-scale low-mode sampling can use a large amount of memory. If memory issues are encountered, consider eliminating the use of solvation. In addition, reducing non-bonded cutoffs also reduces the memory required for the computation. You can do this in the Potential tab by selecting Normal from the Cutoff option menu, or by selecting User defined and entering the appropriate reduced values in the text boxes.

  • Mixed torsional/Large scale low-mode sampling

    This method uses a combination of the random changes in torsion angles and/or molecular position from the MCMM method, together with the low-mode steps from the LLMOD method used in Large scale low-mode. See the MCMM, LMC2, and ARPK opcode descriptions in the MacroModel Command Reference Manual — Contents for detailed descriptions of this method.

Multi-ligand option

Select this option if the input consists of multiple structures that are not conformers. This option is only available for methods that support "serial" searches: Torsional sampling (MCMM), Mixed torsional/Low-mode sampling, and Low-mode sampling.

Perform automatic setup during calculation option

This option allows automatic setup to be performed during the calculation rather than prior to the calculation, with a set of defaults for the search variables. The automatic setup is performed for each structure processed. You can use this option with any of the conformational search methods, but you must use it with serial MCMM searches. By default, it is selected. This option inserts AUTO opcodes into the MacroModel command file. Selecting this option disables the other controls in the CSearch tab for setting up variables.

Perform Automatic Setup button

Automatically generate all the necessary variables for the search. Automatic setup is not available for all conformational search methods; if it is not, this button is dimmed. Perform Automatic Setup applies only to the structures in the Workspace. To set up conformational search variables for other structures, use Perform automatic setup during calculation.

If you perform an automatic setup on an entry that contains a substructure, only the atoms in the substructure are automatically set up with MCMM parameters and comparison atoms. Atoms in fixed and frozen regions are not included in automatic setup.

To clear any previously set conformational search variables before performing an automatic setup, click Reset All Variables.

Reset All Variables button

To reset (i.e. delete all instances of) the conformational search variables, click this button.

Allow inversions of protonated tertiary amines button

To allow chiral protonated tertiary amines to invert during conformational search setup, click this button.

 

Customize the search section

Torsion sampling options option menu

This option menu allows you to control the automatic setup of torsional sampling around some bonds that generally have high barriers. These bonds are the C-N and C-O single bonds in groups like amides and esters, and C=N and N=N double bonds. The four levels of sampling are as follows:

  • Restricted—Do not sample amide and ester derivatives or other planar groups. Torsional constraints are applied to ensure that the relative conformation of these groups is maintained during the MCMM and minimization process. (Sets AUTO arg8=0.)

  • Intermediate—Sample the torsions of amide or ester linkages of nonstandard groups like anhydrides, carbamates, hydrazones, and so on. Normal ester and amide linkages are not sampled, nor are azo and imido linkages. (Sets AUTO arg8=1.)

  • Enhanced—Sample all amide-like and ester-like linkages, including standard amides and esters. Azo and imido linkages are not sampled. (Sets AUTO arg8=2.)

  • Extended—Sample rotations around C=N and N=N bonds, in addition to all amide and ester derivatives. (Sets AUTO arg8=3.)

This option menu is not available if you choose Low-mode sampling or Large scale low-mode sampling for the Method.

Retain mirror-image conformations option

By default, a structure and its mirror image are both considered when comparing with the other structures. If one of the two matches, the structure is eliminated. Select this option to keep both the structure and its mirror image. This option is useful when stereochemistry is critical for the biological function of the molecule, for example.

Search variables option menu and Edit button

From this option menu you can select a search variable type for editing, and click Edit to open the appropriate panel to edit the search variables. If you set up the search using the Perform Automatic Setup button, these panels can be used to view and edit the automated selections. If you choose to specify the search variables manually, select the variable type from the option menu and click the Edit button, then set options for the variable in the panel that opens. Each panel has its own help topic. For more information, see the list below.

Marker display buttons

The Display All Markers and Undisplay All Markers buttons control the display of all markers for the various conformational search variables. Markers for a specific variable can be turned on or off with the Markers or Show markers option in the appropriate panel.

Maximum number of steps text box

This option specifies the number of steps performed in any search. When the number of generated trial structures matches the value in field, the conformational search is terminated.

Use N steps per rotatable bond option and text box

This option restricts the number of steps to a multiple of the number of rotatable bonds. This capability is useful in serial searches, where the number of rotatable bonds can vary between structures. The number of steps is also limited by the value in the Maximum number of steps text box.

Number of structures to save for each search text box

This option specifies the number of unique structures to save for each search, counting from the lowest in energy. A zero value means "save all structures".

Energy window for saving structures text box

This is the threshold value for comparison of trial structures. New structures generated and minimized are kept only if their energy is less than this value above the current global minimum. Lowering this value results in fewer structures saved. The default value is 50 kJ/mol.

Eliminate redundant conformers using options and Cutoff text boxes

Select the distance measure for determining whether structures should be considered equivalent:

  • Maximum atom deviation—consider structures to be different if the maximum atom deviation for any pair of corresponding atoms exceeds the threshold given in the Cutoff text box.

  • RMSD—consider structures to be different if the RMS deviation for all compared atoms exceeds the threshold given in the Cutoff text box.

The default cutoff is 0.5 Å for both options. Unless there are fixed or frozen atoms, the structures are superimposed prior to calculating the distances. The comparison is done if comparison atoms are chosen or Perform automatic setup during calculation is selected.

Low-Mode Options

In the lower portion of the panel, there are three options that are only relevant to the "low-mode" searches, and these are only active when any of the six methods involving low-mode conformational searching is selected.

Probability of a torsion rotation/molecule translation

This option allows the setting of a probability that any defined torsion rotations and molecule translations will be made during the search. This should be a number from 0.0 to 1.0. This option is used with:

  • Mixed torsional/Low-mode sampling
  • Serial torsional/Low-mode sampling
  • Mixed torsional/Large scale low-mode sampling
Minimum distance for low-mode move
Maximum distance for low-mode move

These options are used for setting the minimum and maximum distance for a "low-mode" move. During a search, the fastest moving atom is moved randomly generated distances that are between these two limits. This option is used with all the low-mode methods.

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

The Job Settings button opens the Conformational Search - Job Settings Dialog Box, where you can make settings for running the job.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.

Tutorials

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