Cerius²·Ludi

3       The Ludi interface

The Ludi module contains functionalities that are designed specifically for the modeler interested in developing potential ligands for proteins. The control panels in the Ludi module comprise an interface to the Ludi program suite developed by Dr. Hans Böhm (1992a and 1992b).

This chapter describes in detail the functionality of each control panel of each card in the Ludi module.

Where more detail was thought to be helpful, descriptions of many of the parameters in Ludi have been added to this chapter. As usual, brief, summary descriptions are also available from the Cerius² online help system. To view the online help for a given button or parameter, position your cursor over the control and press the right hand mouse button. A notification window will appear in the center of your monitor's screen containing the help text.

RECEPTOR BASED DESIGN card

Ludi Receptor Based Design control panel

Ludi Load control panel

Ludi Score control panel

Ludi Job Control control panel

Ludi Runtime Parameters control panel

Ludi Active Analog Based Design control panel

Ludi Load control panel

Ludi Job Control control panel

Ludi Runtime Parameters control panel

Ludi Library Specification control panel

Ludi Link/De Novo Library Filters control panels

Ludi Add Library Entry control panel

The Ludi deck of cards will appear containing the following cards:

• ACTIVE SITE VIEWER

• LUDI LIBRARY

• ANALOGS BASED DESIGN

• RECEPTOR BASED DESIGN

Note that clicking the titles of any of these cards will bring the selected card to the top of the deck.

On each of the cards are listed a number of menu items. Clicking a menu item on a card will open the corresponding control panel.

For example, click the ANALOGS BASED DESIGN card to bring it to the fore. Now click the Find Hits button. The Ludi Active Analog Based Design control panel appears containing the most frequently used commands and parameters necessary for performing a Ludi analogs based design job.

There is some redundancy in the organization of the cards. Both the Job Control and Preferences menu items display the same control panels whether invoked in the RECEPTOR BASED DESIGN or ANALOGS BASED DESIGN cards and their settings apply in both cards.

Additionally, for convenience some control panels have buttons which allow you to access other control panels. For example, both Ludi Design control panels have buttons which can launch the Ludi Library Specification and Ludi Runtime Parameters control panels.

RECEPTOR BASED DESIGN card

Ludi Receptor Based Design control panel

Find Ludi hits

The Find Ludi hits button launches a Ludi receptor based run. Ludi searches a database of fragments and suggests those that it thinks have the most potential for being part of a ligand. If the Ludi job is running in background mode, you can check on its progress using the Ludi Job Control control panel.

Run Name

The value of the Run Name parameter is used to name the files produced during a Ludi run and the directory that is created to contain the run results. Each file name has a prefix that matches the Run Name parameter's value and an extension that identifies the content of the file. Cerius² suggests a run name, by default, that contains the current date and time. This virtually guarantees that the run name is unique from one execution of Ludi to the next. You may, of course, replace the default value with your own run name.

Define ___ Model as Receptor (Current/ Selected)

This parameter specifies the protein in whose active site a potential ligand is to be built. You may either indicate the desired receptor by selecting it or making it the current model. Then click the Define button to set it as the receptor. The model name will be displayed in the panel.

Search Sphere Radius

The Search Sphere Radius parameter specifies the radius of the search sphere around the Search Sphere Center Coordinates.

Search Sphere Center Coordinates

The Search Sphere Center Coordinates specify the center of the sphere in which Ludi looks for interaction sites.

Define Center From ___ Atoms (Selected, Active Site)

Because it is generally difficult to know the coordinates in a given space of a point on the screen, the Search Sphere Center Coordinates are typically filled in by picking an atom or atoms and clicking the Define Center from Selected Atoms to convert the pick(s) into a coordinate value in the right space.

Alternatively, you can define an active site with The Active Site Viewer and use it to specify the Search Sphere Center Coordinates. If an active site is defined and the Define Center From Active Site Atoms button is clicked, the coordinates of the geometric mean of the active site atoms is entered for the Search Sphere Center Coordinates.

Display Center

When this button is checked, the point identified by the Search Sphere Center Coordinates is displayed with cross hairs (if you have trouble seeing the cross hairs, try zooming in on the model by pressing the two rightmost buttons of your mouse and dragging across the model window).

Maximum RMS

At each receptor interaction site there is some range of interaction geometry between the ligand and receptor that maximizes the interaction. Deviation from this maximum, therefore, constitutes a measure of the quality of fit. Poor fits have high deviations and good fits have low deviations. As Ludi fits each fragment to the interaction sites, the root mean square of the deviations is computed. For most fragments, if the root mean square deviation exceeds the value of Maximum RMS, the fragment is discarded. If Ludi is trying to fit a large fragment, it may allow the RMS to exceed the value of the Maximum RMS parameter.

When the Link Sites parameter is unchecked, the Maximum RMS is typically set to a value between 0.3 and 0.5. For other settings of the Linkage parameter, set the Max RMS to a value between 0.4 and 0.6.

Values that are larger than those recommended cause more fragments to be suggested by Ludi, while smaller values yield fewer fragments.

Link Sites

When this button is checked, the parameters for setting the linkage method and the Maximum Alignment Angle are visible, and Find Hits will launch a link mode run.

Define ___ from Selected Model (Single Links/Double Links/Links)

The linkage parameter controls how Ludi selects fragments based on their fit to the ligand's link sites. For Single Links and Double Links, only X-H bonds in the proximity of the point specified by the Search Sphere Center Coordinates are considered.

If the linkage parameter is set to Single Links, then fragments are chosen that fit at least one link site. Select a model and then click the Define button. The model name will be displayed in the panel.

If the linkage parameter is set to Double Links, then fragments are chosen that simultaneously fit at least two link sites. Select a model and then click the Define button. The model name will be displayed in the panel.

If the linkage parameter is set to Links, you determine the link sites to be considered. Ludi will find fragments that fit at least one of the specified link sites. Select the link atoms and then click the Define button. You can list the selection by clicking the List button.

Maximum Alignment Angle

The Maximum Alignment Angle is used to limit the search for fragments when the linkage parameter is set to Single Links, Double Links, or Links. Only those fragments whose alignment angle to the link site equals or is less than the Maximum Alignment Angle value are selected.

The alignment angle is formed by a bond in the fragment and the X-H bond that defines the link site in the partially built molecule.

A value between 12° and 14° is recommended for most applications.

Define Selected Atoms as Target Atoms

This control allows you to specify target atoms, i.e., receptor atoms with which fragments are required to interact.

To set the target atoms, select the desired target atoms in the model and click the Define button. To list the current set of target atoms to the textport, click the List button. To clear the current set of target atoms, click the Clear button.

___ Scoring Function (Energy_Estimate/Hbond_ Lipo)

The Scoring Function parameter specifies the scoring function Ludi uses to prioritize the fragment hits for receptor-based runs.

When the Scoring Function parameter is set to Hbond_Lipo, the original Ludi scoring function is used. Each fragment is evaluated as a function of the potential number of hydrogen bonding and hydrophobic contacts it can make with a receptor.

When the Scoring Function parameter is set to Energy_Estimate, a scoring function is used that estimates the change in free energy upon binding the fragment to the receptor. Each fragment is evaluated as a function of the potential number of hydrogen bonding, hydrophobic and ionic contacts it can make and an estimate is made of the penalty due to freezing the internal degrees of freedom of the ligand.

Bond Rotation: ___ (None/ One at a Time/Two at a Time)

The Bond Rotation parameter indicates whether Ludi should generate multiple conformations for the library fragments by rotating about rotatable bonds. The conformations are generated if Bond Rotation is set to any value other than None.

If Bond Rotation is set to None only the conformation entered in the library is used.

If Bond Rotation is set to One at a Time conformations are generated by rotating each rotatable bond without changing the angle of other rotatable bonds in the fragment.

If Bond Rotation is set to Two at a Time, rotatable bonds are altered in pairs to generate new fragment conformations.

Invert Coordinates

The Invert Coordinates parameter indicates whether Ludi should generate and fit both the fragments in the library and their enantiomers. Invert Coordinates is unchecked by default.

Library Spec...

Launches the Ludi Library Specification control panel.

Preferences...

Launches the Ludi Runtime Parameters control panel.

Ludi Load control panel

Load

The Load button loads into Cerius² the results of previous executions of a Ludi run. For a receptor based design, you can load Hits or Interaction Sites. The results, including scoring information, may be loaded into the score table or into a QSAR Study Table. You may also load only a portion of the hits for a run.

Hydrogen bonds between the receptor and hits are generated at load time if Generate Hydrogen Bonds is checked. The hydrogen bonds are visible when the model windows are in overlay mode.

Use the help text to guide you in setting the parameters for this panel (see above).

Ludi Score control panel

Score Ligand-Receptor Interaction

This button launches a job which calculates a score for a docked receptor-inhibitor complex. The Energy_Estimate_1 scoring function is used.

The score is loaded into a score table or the QSAR study table when the calculation finishes.

Scores calculated with the Ludi Score control panel may be slightly different than scores calculated simply by executing a Ludi run since the lipophilic surface portion of the score is dependent on the choice of the center of the complex. The Ludi Score control panel calculates the center of the complex, however, a normal Ludi run launched from one of the Ludi Design control panels uses the value of the Search Sphere Center Coordinates. The differences are smaller than the precision in the calculation.

Use the help text to guide you in setting the parameters for this panel (see above).

Ludi Job Control control panel

The Ludi Job Control control panel allows you to set up background jobs to run concurrently or interactively with Cerius². You are given the choice of whether to send background jobs to a local or remote host (Hosts). You may also choose to run the job in INTERACTIVE or BACKGROUND Run Modes.

In Interactive Mode, Cerius² will not accept further commands until the job finishes. In Background Mode, you may continue with Cerius² while the job runs.

This control panel is generic and is found in many Cerius² modules that run background jobs. Use the help text to guide you in setting the parameters for this panel (see above).

Ludi Runtime Parameters control panel

The Ludi Runtime Parameters control panel allows you to fine tune Ludi runs. On this control panel, you set run-time parameters that control the generation of interaction sites and set rejection criteria.

Preselect

The Preselect parameter controls the Ludi algorithm for selecting the combination of interaction sites onto which a fragment is fit. Ludi searches the list of interaction sites by distance criteria for suitable pairs, triplets, and quadruplets to match the fragments. For each set of interaction sites, the distances between interaction sites are compared to the fragment's corresponding intramolecular distances. For any corresponding pair of interaction site distance and fragment intramolecular distance, if the difference between the two is greater than the product of the values of the Preselect parameter and the Maximum RMS parameter on the Ludi Design control panel then the fragment is not fit to that set of interaction sites.

Recommended values for Preselect are between 1.5 and 2.5. Values larger than this tend to increase the time it takes for Ludi to fit fragments but can increase the number of fragments that Ludi is able to suggest. Values smaller than this speed up the Ludi program at the expense of sometimes missing a potentially useful fragment.

Density of Lipophilic Sites

When Ludi finds an interaction site, it populates the site with points or vectors that represent the geometry of the site. The Density of Lipophilic Sites parameter specifies how dense Ludi should make the population of points in interaction sites for lipophilic atoms.

Too large a value for the Density of Lipophilic Sites parameter slows down the Ludi program though it increases the chances of finding suitable fragments.

A value between 10 and 25 is recommended.

Density of Polar Sites

When Ludi finds an interaction site, it populates the site with points or vectors that represent the geometry of the site. The Density of Polar Sites parameter specifies how dense Ludi should make the population of vectors in interaction sites for hydrogen bonds.

Too large a value for the Density of Polar Sites parameter slows down the Ludi program though it increases the chances of finding suitable fragments.

A value between 15 and 25 is recommended.

Aliphatic_Aromatic

The Aliphatic_Aromatic parameter indicates whether Ludi distinguishes aliphatic and aromatic lipophilic interactions.

If the parameter is checked, then aliphatic atoms in the fragments are matched only with aliphatic atoms in the receptor. Likewise, aromatic atoms in the fragments are matched only with aromatic atoms in the receptor.

If the parameter is unchecked, then lipophilic atoms in the fragments being considered are matched up with lipophilic atoms in the receptor, regardless of whether those lipophilic atoms are aliphatic or aromatic

Fitting Weights

The Link Weight, Lipo Weight and Polar Weight parameters specify relative weighting factors for the three categories of fit for the fragment being considered. Link Weight gives the relative weight for aligning the new fragment with link sites on the ligand. Lipo Weight gives the relative weight for aligning the new fragment with the lipophilic interaction sites and Polar Weight gives the relative weight for aligning the new fragment with the hydrogen bond interaction sites.

For example, to favor good alignment of hydrogen bonds over alignment with link sites on the ligand or with the lipophilic interaction sites, you would set Polar Weight higher than Link Weight or Lipo Weight. Increasing Link Weight by a factor of 2 is effective. Polar Weight and Lipo Weight must be increased by a factor of 10 to be effective.

Reject Bifurcated

The Reject Bifurcated button indicates whether or not you want bifurcated hydrogen bonds to be avoided. A bifurcated hydrogen bond is one in which an acceptor is symmetrically paired with two donors or vice versa.

If the Reject Bifurcated parameter is checked, bifurcated hydrogen bonds will not be allowed.

No Unpaired Polar

The No Unpaired Polar button indicates whether Ludi should reject fits that bury unpaired polar groups on either the fitted fragment or the receptor.

If the No Unpaired Polar parameter is checked, any fit that buries a unpaired polar group is rejected.

Electrostatic Check

The Electrostatic Check button indicates whether Ludi should check for electrostatic repulsion between polar atoms.

This parameter should be unchecked if fragments are being fit at metal ion coordination sites.

See the Minimum Distance parameter for more details.

Minimum Distance

The Minimum Distance parameter specifies the minimum distance (in angstroms) that must separate a polar hydrogen in a fragment from a polar hydrogen in the receptor. If the distance between the two hydrogens is less than the value of Minimum Distance, the fragment is discarded.

Similarly, the distance separating polar oxygen pairs or oxygen/nitrogen pairs is compared to the value of Minimum Distance plus 0.8.

A value of 2.5 is recommended for the Minimum Distance parameter.

Note that the value of Minimum Distance is used only if the Electrostatic Check parameter is checked.

Minimum Separation

The Minimum Separation parameter specifies the minimum distance (in angstroms) that must separate intermolecular pairs of carbon atoms.

As Ludi considers each library fragment, it fits the fragment onto the interaction sites then checks that the fragment carbon atoms do not overlap receptor carbon atoms. Pairs of carbon atoms whose centers are separated by a distance less than or equal to the specified Minimum Separation are considered to have undesirable overlap.

Although the value for the Minimum Separation parameter only pertains to pairs of carbons, Ludi derives threshold distances for other atom pairs from it and checks all intermolecular pairs for overlap. The threshold distances for noncarbon atoms are obtained by scaling the value of the Minimum Separation parameter in a manner consistent with the relative sizes of the carbon and noncarbon van der Waals radii.

A value between 3.0 and 3.5 is recommended for the Minimum Separation parameter.

Minimum Surface

The Minimum Surface parameter specifies a minimum percentage of surface area contact between the fragment and receptor. When Ludi considers whether it is appropriate to suggest a particular fragment, one of things it considers is the percentage of the fragment surface area that is in contact with the receptor. If this percentage is less than the value specified in the Minimum Surface parameter, then the fragment is discarded.

A value of 70, for example, means that only those fragments whose surfaces are 70% in contact with receptor will be suggested by Ludi. A value of zero for this parameter means that surface area contact is not a criterion for considering the appropriateness of a fragment.

If Ludi is recommending too many fragments and you wish to pare down the suggestions, you can increase the value of the Minimum Surface parameter. The algorithm that Ludi uses to calculate the surface area yields only approximate values, so the Minimum Surface parameter should be viewed as a rough paring method. Naturally, since this value is a percentage, it should range between 0 and 100.

Minimum Score

The Minimum Score parameter specifies the smallest allowable score for a fragment fit. Ludi will only suggest fragments with scores greater than the value of Minimum Score.

The default for Minimum Score is 0.

Maximum Unfilled Cavity

The Maximum Unfilled Cavity parameter specifies the maximum size for buried cavities produced by a fragment fit. If the value of Maximum Unfilled Cavity is larger than 0, Ludi will search for buried cavities after fitting a fragment, and, if the cavity is larger than the value specified for Maximum Unfilled Cavity, the fit will be rejected.

The size of the cavity is determined by the number of unoccupied cubic angstrom cubes between the protein and the ligand with no connection to bulk solvent. The value of Maximum Unfilled Cavity should be supplied as an integer in units of cubic angstroms. This check is not done if the value of Maximum Unfilled Cavity is 0.

The default for Maximum Unfilled Cavity is 0.

Maximum Hits

The Maximum Hits parameter specifies the maximum number of fragment fits Ludi will suggest. When the number of accepted fragment fits equals the value of the Maximum Hits parameter, Ludi discontinues searching the fragment library.

ANALOGS BASED DESIGN card

Ludi Active Analog Based Design control panel

Note that this panel is similar but not the same as the Ludi Receptor Based Design control panel. Most notably the target atoms and scoring function parameters do not appear on this control panel.

Find Ludi hits

The Find Ludi hits button launches a Ludi analogs based run. Ludi searches a database of fragments and suggests those that it thinks have the most potential for being part of a ligand. If the Ludi job is running in background mode you can check on its progress using the Ludi Job Control control panel.

Run Name

The value of the Run Name parameter is used to name the files produced during a Ludi run and the directory that is created to contain the run results. Each file name has a prefix that matches the Run Name parameter's value and an extension that identifies the content of the file. Cerius² suggests a run name, by default, that contains the current date and time. This virtually guarantees that the run name is unique from one execution of Ludi to the next. You may, of course, replace the default value with your own run name.

Define ___ Model as Active Analog (Current/ Selected)

This parameter specifies the protein in whose active site a potential ligand is to be built. You may either indicate the desired analogs by selecting them or specifying that All models are analogs. Then click the Define button to set the definition.

Search Sphere Radius

The Search Sphere Radius parameter specifies the radius of the search sphere around the Search Sphere Center Coordinates. Generally, the radius should be large enough to encompass the analogs.

Search Sphere Center Coordinates

The Search Sphere Center Coordinates specify the center of the sphere in which Ludi looks for interaction sites.

Define Center From ___ Atoms (Selected, Active Site)

Because it is generally difficult to know the coordinates of a point on the screen, the Search Sphere Center Coordinates are typically filled in by picking an atom or atoms and clicking the Define Center from Selected Atoms to convert the pick(s) into a coordinate value.

Display Center

When this button is checked, the point identified by the Search Sphere Center Coordinates is displayed with cross hairs (if you have trouble seeing the cross hairs, try zooming in on the model by pressing the two rightmost buttons of your mouse and dragging across the model window).

Maximum RMS

At each receptor interaction site there is some range of interaction geometry between the ligand and receptor that maximizes the interaction. Deviation from this maximum, therefore, constitutes a measure of the quality of fit. Poor fits have high deviations and good fits have low deviations. As Ludi fits each fragment to the interaction sites, the root mean square of the deviations is computed. For most fragments, if the root mean square deviation exceeds the value of Maximum RMS, the fragment is discarded. If Ludi is trying to fit a large fragment, it may allow the RMS to exceed the value of the Maximum RMS parameter.

When the Link Sites parameter is unchecked, the Maximum RMS is typically set to a value between 0.3 and 0.5. For other settings of the Linkage parameter, set the Max RMS to a value between 0.4 and 0.6.

Values that are larger than those recommended cause more fragments to be suggested by Ludi, while smaller values yield fewer fragments.

Link Sites

When this button is checked, the parameters for setting the linkage method and the Maximum Alignment Angle are visible, and Find Hits will launch a link mode run.

Define ___ from Selected Model (Single Links/Double Links/Links)

The linkage parameter controls how Ludi selects fragments based on their fit to the ligand's link sites. For Single Links and Double Links, only X-H bonds in the proximity of the point specified by the Search Sphere Center Coordinates are considered.

If the linkage parameter is set to Single Links, then fragments are chosen that fit at least one link site. Select a model and then click the Define button. The model name will be displayed in the panel.

If the linkage parameter is set to Double Links, then fragments are chosen that simultaneously fit at least two link sites. Select a model and then click the Define button. The model name will be displayed in the panel.

If the linkage parameter is set to Links, you determine the link sites to be considered. Ludi will find fragments that fit at least one of the specified link sites. Select the link atoms and then click the Define button. You can list the selection by clicking the List button.

Maximum Alignment Angle

The Maximum Alignment Angle is used to limit the search for fragments when the linkage parameter is set to Single Links, Double Links, or Links. Only those fragments whose alignment angle to the link site equals or is less than the Maximum Alignment Angle value are selected.

The alignment angle is formed by a bond in the fragment and the X-H bond that defines the link site in the partially built molecule.

A value between 12° and 14° is recommended for most applications.

Bond Rotation: ___ (None/ One at a Time/Two at a Time)

The Bond Rotation parameter indicates whether Ludi should generate multiple conformations for the library fragments by rotating about rotatable bonds. The conformations are generated if Bond Rotation is set to any value other than None.

If Bond Rotation is set to None only the conformation entered in the library is used.

If Bond Rotation is set to One at a Time conformations are generated by rotating each rotatable bond without changing the angle of other rotatable bonds in the fragment.

If Bond Rotation is set to Two at a Time, rotatable bonds are altered in pairs to generate new fragment conformations.

Invert Coordinates

The Invert Coordinates parameter indicates whether Ludi should generate and fit both the fragments in the library and their enantiomers. Invert Coordinates is unchecked by default.

Library Spec...

Launches the Ludi Library Specification control panel.

Preferences...

Launches the Ludi Runtime Parameters control panel.

Ludi Load control panel

Note that this panel is the same as that available on the RECEPTOR BASED DESIGN card.

Load

The Load button loads into Cerius² the results of previous executions of a Ludi run. You can load Hits, Interaction Sites, or the Analogs Shell. The results, including scoring information, may be loaded into the default browser or into a QSAR Study Table. You may also load only a portion of the hits for a run. Generate Hydrogen Bonds should be unchecked when loading results from an analog based run.

Use the help text to guide you in setting the parameters for this panel (see above).

Ludi Job Control control panel

The Ludi Job Control control panel allows you to set up background jobs to run concurrently or interactively with Cerius². You are given the choice of whether to send background jobs to a local or remote host (Hosts). You may also choose to run the job in INTERACTIVE or BACKGROUND Run Modes.

In Interactive Mode, Cerius² will not accept further commands until the job finishes. In Background Mode, you may continue with Cerius² while the job runs.

This control panel is generic and is found in many Cerius² modules that run background jobs. Use the help text to guide you in setting the parameters for this panel (see above).

Ludi Runtime Parameters control panel

The Ludi Runtime Parameters control panel allows you to fine tune Ludi runs. On this control panel, you set run-time parameters that control the generation of interaction sites and set rejection criteria.

Preselect

The Preselect parameter controls the Ludi algorithm for selecting the combination of interaction sites onto which a fragment is fit. Ludi searches the list of interaction sites by distance criteria for suitable pairs, triplets, and quadruplets to match the fragments. For each set of interaction sites, the distances between interaction sites are compared to the fragment's corresponding intramolecular distances. For any corresponding pair of interaction site distance and fragment intramolecular distance, if the difference between the two is greater than the product of the values of the Preselect parameter and the Maximum RMS parameter on the Ludi Design control panel then the fragment is not fit to that set of interaction sites.

Recommended values for Preselect are between 1.5 and 2.5. Values larger than this tend to increase the time it takes for Ludi to fit fragments but can increase the number of fragments that Ludi is able to suggest. Values smaller than this speed up the Ludi program at the expense of sometimes missing a potentially useful fragment.

Density of Lipophilic Sites

Applies only to receptor based runs.

Density of Polar Sites

Applies only to receptor based runs.

Aliphatic_Aromatic

The Aliphatic_Aromatic parameter indicates whether Ludi distinguishes aliphatic and aromatic lipophilic interactions.

If the parameter is checked, then aliphatic atoms in the fragments are matched only with aliphatic atoms in the receptor. Likewise, aromatic atoms in the fragments are matched only with aromatic atoms in the receptor.

If the parameter is unchecked, then lipophilic atoms in the fragments being considered are matched up with lipophilic atoms in the receptor, regardless of whether those lipophilic atoms are aliphatic or aromatic

Fitting Weights

The Link Weight, Lipo Weight and Polar Weight parameters specify relative weighting factors for the three categories of fit for the fragment being considered. Link Weight gives the relative weight for aligning the new fragment with link sites on the ligand. Lipo Weight gives the relative weight for aligning the new fragment with the lipophilic interaction sites and Polar Weight gives the relative weight for aligning the new fragment with the hydrogen bond interaction sites.

For example, to favor good alignment of hydrogen bonds over alignment with link sites on the ligand or with the lipophilic interaction sites, you would set Polar Weight higher than Link Weight or Lipo Weight. Increasing Link Weight by a factor of 2 is effective. Polar Weight and Lipo Weight must be increased by a factor of 10 to be effective.

A link site is a site on the partially-built candidate ligand at which building can continue. Ligand bonds of the variety X-H (a covalent bond between hydrogen and some other atom) are considered suitable link sites. For more detail on link sites, please see the Theory section.

Reject Bifurcated

Applies only to receptor based runs.

No Unpaired Polar

Applies only to receptor based runs.

Electrostatic Check

Applies only to receptor based runs.

Minimum Distance

Applies only to receptor based runs.

Minimum Separation

Applies only to receptor based runs.

Minimum Surface

Applies only to receptor based runs.

Minimum Score

The Minimum Score parameter specifies the smallest allowable score for a fragment fit. Ludi will only suggest fragments with scores greater than the value of Minimum Score.

The default for Minimum Score is 0.

Maximum Unfilled Cavity

Applies only to receptor based runs.

Maximum Hits

The Maximum Hits parameter specifies the maximum number of fragment fits Ludi will suggest. When the number of accepted fragment fits equals the value of the Maximum Hits parameter, Ludi discontinues searching the fragment library.

LUDI LIBRARY card

The Ludi Library Specification control panel is split into two subpanels, one for a De Novo Library and the other for a Link Library, each containing virtually identical controls and parameters.

Library Type (MSI/USER/ [LUDI/ACD])

There are two basic library types available, MSI and USER. In addition, the De Novo Library subpanel offers LUDI/ACD as an option. For more information about the LUDI/ACD library, see Ludi/ACD in the Theory section.

Choosing MSI indicates that the default library is to be used.

Choosing USER, causes the file browser and Library entry box to be visible allowing you to specify a library from your directories.

file browser

Use the file browser to find and specify the user library topology file.

Library

When SELECT on the file browser is clicked, this entry box initializes to the chosen library file name. You may also edit this box directly without using the file browser.

Search Range

Specifies the library entry with which the Ludi run should start (First) and stop (Last). The entries are identified by their order in the library, e.g., first entry is 1. The last entry in the library may be identified by END.

Filters...

This button is here for convenience and opens the appropriate Ludi Library Filters control panel.

Ludi Link/De Novo Library Filters control panels

The Ludi Library Filter control panels are used to specify additional requirements for the fragments to be considered during a Ludi run. There is one panel for specifying filters for de novo libraries and one for specifying filters for link libraries. Take care to use the correct control panel since they are very similar in appearance.

The filters include lists of atoms and functional groups that are either required or prohibited, formal charges that are required to exist on some group in the fragment, and maximum and minimum size for the fragments. If a fragment does not pass all the filters, no attempt will be made to fit the fragment to the interaction sites.

Filter Lists

The Filter Lists parameter identifies the list to be operated on. There are four filter lists available: Required_Group, Required_Atom, Rejected_Group, and Rejected_Atom.

Any fragment that does not contain all groups in the Required_Group list and all atoms in the Required_Atom list will be rejected.

Any fragment that contains a group in the Rejected_Group list or an atom in the Rejected_Atom list will be rejected.

List Operation

The list operation parameter (a toggle that looks like a minus sign) specifies the action to take on the list identified in the Filter Lists parameter. You may Add or Delete entries. Additionally there are buttons to Clear Selected Filter from the list, or List Selected Filter to the textport.

In the adjacent text field indicate the entry to be added or deleted from the selected library filter list.

Library Fragment Size Limits

Any fragment that has fewer atoms than is specified by the Minimum ___ Atoms parameter or more atoms than is specified by the Maximum ___ Atoms parameter will be rejected.

Clear/List Selected Filter

Use these buttons to Clear all entries from the selected filter or List the selected filter to the textport.

Clear All De Novo Library Filters

Clears all the filter lists and returns numeric filters to their default values.

Ludi Add Library Entry control panel

This control panel allows you to add the current model to either existing or new libraries. This feature is useful for adding a model at a time. To add more than a few models, see the Ludi_Genlib chapter for information about using the Ludi_Genlib program from the UNIX command prompt.

ADD Current Model to ___ Library

Allows you to add the current model to a library.

Format ___

If you choose to create a New library, you are prompted for a format. The choices are MOL_Text, PDB_Text and MOL_Binary. Entries within the same library must all be of the same format.

For MOL_Text and MOL_Binary, the topologies are stored in MDL MOL format and bond orders are retained. The latter file format is unformatted, thereby saving disk space.

For PDB_Text format, the topology is stored in Brookhave Protein Databank format. Bond orders are not retained in this format.

file browser

Use the file browser to find and specify the existing library .struct file.

Library Name

When SELECT on the file browser is clicked, this entry box initializes to the chosen library name. You may also edit this box directly without using the file browser. For example, if you are creating a new library, you must enter a name here.

Label

Each library entry must have a unique three character label identifier.

Set Protonation

When checked, this indicates that protonation states should be automatically set as follows:

COOH COO^-

PO₄H₂ PO₄^2-

PO₄H^- PO₄^2-

NH-C-NH₂ C(NH₂)₂⁺

NH₂ NH₃⁺

SO₃H SO₃^-

When checked, this indicates that link sites should be generated for the fragment in addition to polar and hydrophobic sites. The Define button allows you to specify the method by which link sites will be generated. Definitions are cumulative. The List button lists the link sites to the textport and the Clear button clears all link sites from the current model.

Comment

Allows you to add an annotation to the added library entry.