Embrace Conformational Search Panel

Embrace Conformational Search Panel Features

• Tabs
• Job toolbar
• Status bar

Tabs

• Potential
• Substructure
• Mini
• Embrace
• 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
  • Use customized version option
  • Parameter set button
• Restrain bonds to metals around input geometry option
• Solvent option menu
• Electrostatic treatment option menu
• Dielectric constant text box
• Charges from option menu
• Cutoff option menu and text boxes
• Debugging options text box
• Read Potential Settings from Command File button

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 Waals	7.0
  Electrostatic	12.0
  H-bond	4.0

• Extended: sets the following cutoffs:
  

  Van der Waals	8.0
  Electrostatic	20.0
  H-bond	4.0

• 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.

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
  • Freely moving atoms (substructure) picking controls
  • Expand to atoms within radius of text box
  • Complete residues option
  • Calculate constrained-atom mutual interactions option
• Shells Definition Section
  • Shells (constrained and frozen atoms) list
  • New button
  • Delete button
  • Radius text box
  • Complete residues option
  • Force constant text box
  • Freeze atoms option
  • Additional atoms for shell section
• Input and Output Section
  • Read .sbc File button
  • Write .sbc File button
  • Write ASL formatted .sbc file option
  • Write absolute atom coordinates option
• Atom count

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
• Maximum iterations text box
• Converge on option menu
• Convergence threshold text box

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.

Embrace Tab Features

The Embrace tab contains controls for minimizing the energy of protein-ligand complexes for a series of pre-positioned ligand structures.

• Source of ligands
• Receptor
• Structures saved

Source of ligands

The ligand structures can either come from a file or from the selected entries in the Project Table. If you choose Input file, you can specify a file for the ligand structures by entering the path to the file in the Input file text box or by clicking Browse to navigate to the file. In either case, the structures are written to the file jobname.mae in Maestro's current working directory.

Receptor

To run an Embrace calculation of any kind, you must specify the receptor.

• If you are using an input file, you can do one of the following:
• Select the First structure in file option to use the first structure as the receptor
• Enter an entry name or click Choose to select an entry for the receptor
• If you are using selected entries, you can do one of the following:
• Select the First selected entry option to use the first selected entry as the receptor
• Enter an entry name or click Choose to select an entry

Structures saved

There are three options for how the output structures can be written to the output file:

• Complexes only—minimized ligand-receptor complexes only
• Ligands only—ligand structures extracted from minimized complexes
• Receptor, ligands and complexes—in addition to minimized complexes, the receptor minimized without a ligand and ligands minimized without the receptor are written.

CSearch Tab Features

The Embrace CSearch tab is different from the regular CSearch tab (see CSearch Tab Features), though it has some common features.

• Method option menu
• Number of steps text box
• Number of input conformations available to seed each search text box
• Number of structures to save for each search text box
• Energy window for saving structures text box
• Low-mode text boxes
• Eliminate redundant conformers using options

Method option menu

There are only three methods for performing an Embrace conformational search: Torsional sampling (MCMM), Low-mode sampling, and Mixed torsional/Low-mode sampling.

Low-mode calculations are limited to a few hundred atoms and should be used for systems with smaller ligand/substructure combinations. However, for such systems, low-mode searches can be comparatively efficient. MCMM conformational searches are less memory-intensive, and thus may be used on larger portions of the system provided that the number of degrees of freedom changed at any one time is limited and the substructure carefully selected.

Number of steps

Specify the number of steps to be performed in the search. When the number of generated trial structures matches the value in this field, the conformational search is terminated.

Number of input conformations available to seed each search

Specify the number of input conformations for each ligand. Each ligand in the file must have exactly this number of conformations.

Note: You may have multiple conformers if any of the following are true:

• You used COPY/ALGN at the command line
• You are using a file generated from a conformational search in which a specified number of conformations was kept
• You are using Glide poses as input conformations, with the same number of poses for each ligand.

Number of structures to save for each search

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

Energy window for saving structures

Specify the threshold value for comparison of trial structures. Any 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 500 kJ/mol.

Low-mode text boxes

There are three options that are only relevant to the low-mode searches, and are only active when a method involving low-mode conformational searching is selected.

• Probability of a torsion rotation/molecule translation:

  This option is only used with the Mixed torsional/Low-mode sampling method. Specify the probability that any defined torsion rotations and molecule translations are made at each step during the search. This should be a number from 0.0 to 1.0.

• Minimum distance for low-mode move
  Maximum distance for low-mode move

  Specify 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.

Eliminate redundant conformers using options and Cutoff text boxes

If comparison atoms are chosen or Perform automatic setup during calculation is selected, structures produced during a conformational search are compared to see if they are unique. 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.

 

Job toolbar

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

The Job Settings button opens the Embrace 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.

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.

Related Topics

• Embrace Minimization Panel
• Embrace Conformational Search - Job Settings Dialog Box