Ligand_Optimization Setup Parameter Block

Lig. Partition Opts: Partition-Method

enumerated choices: {Calculate|Dictionary}

HINT offers two methods of partitioning the ligand on this option menu: "Calculate" or "Dictionary". The Calculate method uses the molecule's potential types (CVFF) and bond connections as input data to the partition algorithm. This technique is most appropriate for small organic molecules such as ligands, substrates or drugs. The Dictionary method relies on a predefined set of predefined data for regularly occurring substructures or monomers such as amino acid residues and nucleic acid bases. In this case the input data is the atom names and substructure names/types.

Lig. Partition Opts: Solvent-Condition

enumerated choices: {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.

Lig. Partition Opts: Hydrogen-Treatment

enumerated choices: {Retain_All|Polar_Only|United_Atom}

This menu describes how the Partitioning will treat hydrogens; there are three options: "United_Atom" (using an approach the treats all hydrogens implicitly as part of their parent heavy atom), "Polar_Only" (using an approach that treats (only) polar hydrogens explicitly), and "Retain_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_Atom option is chosen. In general the Polar_Only option is best for most applications. The Retain_All option appears to "dilute" the hydrophobic density, but treats aromatic hydrogens as potential hydrogen bond donors.

Lig. Partition Opts: Polar-Proximity

enumerated choices: {Off|Via_Bonds|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.

Lig. Partition Opts: Thru-Space-Function

enumerated choices: {I exp(-Jr)|I/r**J}

Choose the functional form for Through_Space Polar Proximity. Two options are provided: a exponential and a power function. Each has two parameters that can be used to generate a wide range of functional behavior.

Lig. Partition Opts: I:

real number

I is a parameter used to tailor the functional behavior of Through_Space Polar Proximity.

Lig. Partition Opts: J:

real number

J is a parameter used to tailor the functional behavior of Through_Space Polar Proximity.

Optimization Optns: Cut-Off Radius

real number

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 Optns: Van der Waals Limit

real number

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 Optns: Translation Limit

real number

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 Optns: Convergence

real number

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 Optns: Speed

slider: 1 -> 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. This version (2.30I) of HINT has the slider varying between 0 and 1; the integer value is approximately 6 times the value reported by the parameter.