View HINTSCORE: Add Columns Dialog Box

HINTSCORE: Add Columns Dialog Box

Calculation Type

radios: {InterMolecular [Ligand each row]|IntraMolecular [each row]}

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

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

IntraMolecular [each row] will calculate an IntraMolecular Hint Score for each conformer or molecule 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 Options for rows: Partition Method

radio button set: {Calculate|Dictionary}

HINT offers two methods of partitioning the ligand molecules 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 for rows: 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 for rows: 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 for rows: 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 for rows: 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.

Partition Options for rows: Direction Vectors/Parameters...

check box and push button

>Use these options to activate directionality vectors for the molecule (row) partitions. Pressing the Parameters button calls the Direction Vector dialog box.

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 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.

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.