View HINTSCORE: Add Columns Dialog Box

HINTSCORE: Add Columns Dialog Box

Calculation Type

radios: {InterMolecular [each Ligand (row)]|InterMolecular [with Prototype Conformer]|IntraMolecular [requires Prototype]}

These three options refer to the different ways the HintScore calculation can proceed:

InterMolecular [each Ligand (row)] will take each row of the MSS as a unique ligand (different molecule) and calculate a Score for it, against a common rigid receptor.

InterMolecular [with Prototype Conformer] will take each row as a conformation of the same molecule (i.e., Prototype) and calculate a Score for it, against a common rigid receptor.

IntraMolecular [requires Prototype] will calculate an IntraMolecular Hint Score for each conformation of the Protoype in the Molecular Spreadshhet.

Partition Receptor

push button

Two components are necessary for the InterMolecular HINTSCORE Functions: a Macromolecule in a Sybyl Molecular area, and a Molecular Spreadsheet of ligands oriented for interaction with the common receptor (Macromolecule). Pressing this button calls the HINT Partition Molecule dialog to Partition the Macromolecule.

Partition Prototype

push button

This button Partitions a prototype of either the Ligand molecule, for "InterMolecular [with Prototype Conformer]", or for the molecule being examined with "IntraMolecular [requires Prototype]". Pressing this button calls the HINT Partition Molecule dialog.

Partition Options: Partition Method

radio button set: {Calculate|Dictionary}

HINT offers two methods of partitioning the ligand moleculesx on this option menu: "Calculate" or "Dictionary". The Calculate method uses the molecule's atom types (Sybyl) and bond connections as input data to the partition algorithm. The Dictionary method relies on a predefined set of predefined data for regularly occurring substructures such as amino acid residues and nucleic acid bases. In this case the input data is the atom names and substructure names/types.

Partition Options: Hydrogen Treatment

option menu: {United|Essential|All}

This menu describes how the Partitioning will treat hydrogens; there are three options: "United" (using an approach the treats all hydrogens implicitly as part of their parent heavy atom), "Essential" (using an approach that treats (only) polar hydrogens explicitly), and "All". Note that the selection of this parameter has implications in following interaction calculations. For example, hydrogen bonding will be incorrectly modeled by HINT if the United option is chosen. In general the Essential option is best for most applications. The All option appears to "dilute" the hydrophobic density, but treats aromatic hydrogens as potential hydrogen bond donors.

Partition Options: Solvent Condition

option menu: {Inferred|Neutral|Acid|Base}

This option menu is active only if the "Dictionary" method is chosen. The menu lists four options: "Inferred", "Neutral", "Base", "Acid". The latter three represent the pH conditions under which the molecule is to be partitioned. Inferred represents a special case where each substructure (e.g., residue) will be partitioned based on its hydrogen count. For example, if one aspartic acid in a protein is believed to be protonated while other acidic and basic residues are to remain at neutral pH, using the Inferred Solvent Condition is the appropriate approach. Note that all essential hydrogens must be present in the entire model, not just in the "special" residues.

Partition Options: Polar Proximity

option menu: {Off|Via_Bond|Through_Space}

This option menu is only active if the "Calculate" method is chosen. When two or more polar groups are in "in proximity" within a molecule, their effects are cumulatively diminished -- this is termed the polar proximity effect and is dealt with by the Leo method of LogP estimation and by HINT as corrective factors to the hydrophobic atom constants. HINT offers three options for Polar Proximity: "Off", "Via_Bond", and "Through_Space". The Via_Bond method is most compatible with the Leo system, and is the option recommended. Through_Space may be appropriate for some larger molecules that have significant intramolecular non-covalent interactions between polar groups. It uses a through-space distance function to estimate the polar proximity effect.

Partition Options: Through Space Function...

push button

This button, which is only active if Polar Proximity is chosen to be Through_Space, calls the Polar Prox. Dist. dialog to define the specific through-space distance function to be applied to the polar proximity correction.

Distance Function...

push button

Select this button to describe the mathematical distance behavior of hydropathy for the current calculation. This button calls the Distance Function dialog box.

Table File Root

text

Enter a text file name to be used as the "root" of each HintTable created by this command. Each individual file will be named as a derivative of this root name.

Table Control: Save HintTables for each Row

check box

If you wish the HintTables to be saved to disk for each row of the MSS, turn this option on; otherwise a summary table and the values stored in the MSS will be the only record of the calculation.

Table Control: IntraMonomer

check box

The IntraMonomer parameter specifies whether IntraMolecular interactions within the same monomer or substructure are to be recorded by the HintTable or map.

Table Control: Cut Off Radius

field

The Cut Off Radius parameter represents a method to reduce calculation time for HINT calculations. If the distance between two atoms (for HintTable calculations) or between a grid point and an atom (for map calculations) exceeds the cutoff-radius that interaction is ignored. Cut Off Radius values of greater than 6.0 Angstroms appear to have minimal effect on the calculation quality but can save considerable calculation time.

Table Control: Van der Waals Limit

field

The Van der Waals Limit parameter allows limited user control of the HINT Van der Waals radii set. The Van der Waals Limit is a multiplicative factor (default = 1.00) that adjusts the predefined radii set. A value of less than 1 would allow more "bump" between atoms, while a value greater than one would allow less.

Table Control: Proton Suppress

check box

The Proton Suppress parameter specifies whether hydrogens are to be represented explicitly in the HintTable (Off) or incorporated into their associated heavy atom (On). In most experimental studies involving proteins, only the heavy atoms are known precisely and hydrogen atom positions are modeled. Regardless of Proton Suppress all interactions involving hydrogens are individually made; the difference is only how this data is tabulated. One consequence of Proton Suppress is the definition of hydrogen bonds. If Proton Suppress is On, hydrogen bonds are characterized by a heavy atom-heavy atom distance. If Proton Suppress is Off, hydrogen bonds are characterized by hydrogen-heavy atom distances.

H-Bnd Distance X-H

field

This parameter, H-Bnd Distance X-H describes the distance below which a polar hydrogen/hydrogen bond acceptor interaction is classified as a Hydrogen Bond. Above this value the interaction is classified as Acid/Base.

H-Bnd Distance X-Y

field

This parameter, H-Bnd Distance X-Y describes the distance below which a hydrogen bond donor/hydrogen bond acceptor interaction is classified as a Hydrogen Bond. Above this value the interaction is classified as Acid/Base.

Table Control: Output Radius

field

The Table Extents parameters are used to filter the quantity of data written to the HintTable file. Without filtering the HintTable can become exceedingly large. For instance, a interaction calculation between two subunits of a protein, each possessing 10^3 atoms would yield 10^6 data records in an unfiltered HintTable. Interactions between atoms that are farther apart than the Output Radius parameter are not written to the file.

Table Control: Output Value

field

Interactions between atoms that have a HINT interaction score of less than the Output Value parameter are not written to the HintTable File.

Table Control: Table Resolution

radios: {Low|High}

This parameter controls the number of significant figures reported for each HINT score item.

Low reports zero digits after the decimal place.

High reports five digits after the decimal place.

MSS Output Options

check boxes

Choose the type(s) of HINTScore data to be added to the Molecular Spreadsheet. Each selected data type will add a column to the spreadsheet which will be filled with the appropriate data type for each row as the calculation progresses.

Total HINT Score is the sum of all atom-atom interactions between the selected atoms in the Macromolecular Receptor and ligand(s).
Hydrogen Bond HINT Score is the sum of all interactions that HINT characterizes as being Hydrogen Bonds (see Proton Suppress, above).
Hydro./Hydro. HINT Score is the sum of all hydrophobic-hydrophobic interactions.
Acid/Base HINT Score is the sum of all interactions that HINT characterizes as being Lewis Acid/Base. Note that in the HINT model, hydrogen bonds are a special case of acid/base interactions and that modification of the Proton Suppress options directly impacts this definition.
Base/Base HINT Score is the sum of all interactions that HINT characterizes as being Lewis Base/Base.
Acid/Acid HINT Score is the sum of all interactions that HINT characterizes as being Lewis Acid/Acid.
Hydro./Polar HINT Score is the sum of all interactions that HINT characterizes as being between a hydrophobic atom and a polar atom. Note that these last three categories are generally unfavorable interactions.