View Optimize Small Ligands Dialog Box

Optimize Small Ligands Dialog Box

Ligand Center: radios: {Use picked atom as Ligand Center|Calculate Center-of-Gravity of Ligand}; These two options refer to the different ways the rotational/translational center of the small ligand can be defined.
Select Ligand (atom): push button; Select a single atom representative of the small molecule ligand.
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.
Optimization Control: Cut Off Radius: field; The Cut Off Radius parameter normally represents a method to reduce calculation time for HINT calculations. Here it also indicates the the radius of atoms from the "Site" to be included in the calculation. Cut Off Radius values of greater than 6.0 Angstroms appear to have minimal effect on the calculation quality but can cost considerable calculation time.
Optimization 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.
Optimization Control: Translation Limit: field; The Translation Limit parameter specifies how far from the initial center that the ligand will be allowed to move. This should be a value somewhat consistent with crystallographic B factors, if they are available, i.e., a large B factor would "allow" a larger Translation Limit. The useful range here is probably something like 0.1 - 1.0. Practically, the Translation Limit is the initial radius of the search sphere. (See Theory for more information.)
Optimization Control: Convergence: field; The convergence is the termination point for the translational optimization. When the radius of the search sphere is less than the Convergence, the iterations stop and a final rotational search is performed for the ligand.
Optimization Control: Speed: radios: {1|2|3|4|5|6}; The speed is a parameter whose purpose is to balance the interests of accuracy with the need for speed. The Theory section has a more detailed discussion. Note that the slowest speeds are very slow, on the order of many hours. Speeds of 4 or 5 seem reasonable.
Site Selection: Molecule 1: checkbox and push button; The ligand "binding site" must be selected by choosing one, two, or three molecular areas that have already been partitioned. It is OK for one of these areas to also contain the ligand, as this will be factored out by the algorithm.
Site Selection: Molecule 2: checkbox and push button; The ligand "binding site" must be selected by choosing one, two, or three molecular areas that have already been partitioned. It is OK for one of these areas to also contain the ligand, as this will be factored out by the algorithm.
Site Selection: Molecule 3: checkbox and push button; The ligand "binding site" must be selected by choosing one, two, or three molecular areas that have already been partitioned. It is OK for one of these areas to also contain the ligand, as this will be factored out by the algorithm.
Write HintTable File/FONT>: checkbox and text; Select this command to write a HintTable File for the optimized ligand and its interactions with the Site. Note that this is for the site only, which means that the parameters set elsewhere in this dialog, e.g., Cut Off Radius, etc. apply.