Command Overview
This chapter contains detailed descriptions of the InsightII
user interface for each new command
available within the Hint2.30I module and added by Hint2.30Di.
This chapter is organized in approximately the order you may use
the commands while performing a Hint Study, first by pulldown and
then by command. To find information on a particular command
look first for its pulldown and then for the command. Each command
section is illustrated by a depiction of the associated parameter
block. The Grid pulldown is not described here, it is functionally
identical to the Grid pulldown in other InsightII modules such as
DelPhi.
As with InsightII, Hint commands are organized in a hierarchy. At the
top of the organization are the modules, next are the pulldowns, and at the bottom
of the hierarchy are the commands.
Hint is one of several optional modules available in addition to the
InsightII core modules. The modules typically included with InsightII are
Viewer, Biopolymer, Builder, Docking,
Ampac/Mopac, Discover, and Analysis. Each module is
comprised of pulldowns with related commands.
Next in the command hierarchy, below modules, are pulldowns. When a particular
module is selected, the lower menu bar displays the pulldowns associated with that
module. The Setup pulldown, for example, is a set of all commands used
in the setup of a Hint calculation.
When you are in the Hint module, seven pulldowns are available on the lower
menu bar: Partition, Setup, HintGrid, Grid,
HintTable, Archive Functions, and LockSmith.
Below pulldowns in the command hierarchy are the commands. For example, the
Setup pulldown contains the commands: Grid, HINT DistFunct,
Grid_Molecule, Grid_Interactions, Grid_Complement,
HintTable and Hint_Spreadsheet.
The remainder of this section, organized by pulldown, briefly describes the
functionality of each pulldown and its associated commands. For a more detailed
explanation of a particular command refer to Command Descriptions (Chapter 5 in
this manual).
The Partition pulldown contains commands to "Partition" molecules
(and SMILES strings for Hint2.2Di users). A molecule's partition
is the LogP for octanol/water solubility. This number which has
significance on its own for Medicinal Chemistry and drug design is
reported by the Partition commands. In addition, Partitioning
assigns Hint parameters to molecules for HintGrid, HintTable, and
LockSmith calculations.
The Partition Molecule command calculates Hint hydropathic
parameters for InsightII molecule objects. These parameters are
necessary for further Hint calculations. Each partition operation
yields the LogP for octanol/water partitioning (hydrophobicity)
which is reported by the command.
View Molecule Partition Parameter Block
The Partition SMILES command calculates LogP for octanol/water
partitioning (hydrophobicity) for SMILES strings entered from the
keyboard or from disk files.
View SMILES Partition Parameter Block
The Setup pulldown contains commands which define the Hint
grid and table calculation parameters. Execution of commands in
the HintGrid and HintTable pulldowns retrieves and utilizes the
Setup parameter values.
The Setup Grid command defines and displays the the 3-dimensional
grid used in the Hint calculation. There are three basic
quantities which must be specified to define the grid: the Grid
Center which defines the coordinates around which the grid is
centered, Grid Size which defines the total distance (in Angstroms)
spanned by the grid, and Grid Resolution which refers to the
distance between neighboring grid points.
View Grid Setup Parameter Block
Parameters in the Setup Distance Function command control the functional
form of the HINT calculation with respect to distance between atoms
(for HintTable calculations) or between atoms and grid points (for
Map calculations).
View Distance Function Setup Parameter Block
The Setup Grid_Molecule command defines the parameters necessary
for creation of a Hint Hydropathic field grid that maps the 3D
hydropathy of the molecule. After the parameters are set in this
command, the next step is to use the Molecule command in the
HintGrid pulldown.
View Grid_Molecule Setup Parameter Block
The Setup Grid_Interactions command defines the parameters
necessary for creation of a Hint Interaction grid. This type of
HintGrid allows the visualization of the non-covalent
interactions within (IntraMolecular) or between (InterMolecular)
molecule(s). In Hint interaction maps the spatial region between
interacting atoms or groups is encoded with the type and relative
importance of the interaction. After the parameters are set in
this command, the next step is to use the IntraMolecular or
InterMolecular commands in the HintGrid pulldown.
View Grid_Interactions Setup Parameter Block
The Setup Grid_Complement command defines the parameters
necessary for creation of a Hint Complement grid. This
type of HintGrid allows the extrapolation/visualization of
the 3D hydropathic structure of an unknown species proposed
to be binding to an existing molecule. One example of this
would be to identify the characteristics of a "key" molecule
to fit a known receptor. After the parameters are set in
this command, the next step is to use the Complement command
in the HintGrid pulldown.
View Grid_Complement Setup Parameter Block
HintTable
The Setup HintTable command contains the parameters for both
InterMolecular and IntraMolecular HintTable calculations.
Briefly, a HintTable is a listing of atom-atom interactions
between (or within) a molecule characterized by type and
summarized by a score. The HintTable is a useful diagnostic
tool for investigations of ligand binding, protein folding,
or subunit interactions. After the Setup HintTable command
is completed, the next step is IntraMolecular or InterMolecular
in the HintTable pulldown.
View HintTable Setup Parameter Block
The Setup Hint_Spreadsheet adds the necessary column headings
and properties to a new insightII Spreadsheet for
use in Hint calculations. Currently these spreadsheets
can be used in the HintTable InterMolecular command and with
the IntraMolecular and InterMolecular Table options of the
Archive Functions pulldown.
View Hint_Spreadsheet Setup Parameter Block
Ligand_Optimization
The Setup Ligand_Optimization command contains the parameters for
small molecule ligand position/orientation optimizations using
the Hint Score as a force-field. The actual ligand optimization
command is under the HintTable pulldown as, in effect, this
operation is actually a series of HintTable calculations driven
by a score optimization algorithm.
View Ligand_Optimization Setup Parameter Block
The HintGrid pulldown contains the commands to execute the Hint
map creation for Molecules, InterMolecular and IntraMolecular
interactions, for Complementary species, and to calculate
difference maps from two input maps.
The Molecule HintGrid command creates a Hint hydropathic field
map of the molecule. Regions of hydrophobicity, basicity, and
acidity can be identified. This calculation can be fairly time
consuming for a large molecule where it may be advisable to run
the calculation in the background, but is generally very quick for
small molecules where interactive mode may be preferred.
View Molecule HintGrid Parameter Block
The InterMolecular HintGrid command creates a Hint Interaction
map representing the non- covalent interactions between atoms in
two distinct molecular entities. This may be between two
protein subunits, between a enzyme and its substrate, or etc.
The resulting map allows graphical visualization of favorable and
unfavorable regions of binding between the species. The
algorithm compares, pairwise, atoms in both species for each
defined grid point in the map. Thus it usually is advisable to
run this type of map calculation in the background.
View InterMolecular HintGrid Parameter Block
The IntraMolecular HintGrid command creates a Hint Interaction
map representing the non- covalent interactions between atoms in
a single molecular entity. One example of this calculation would
be in the study of protein folding. The resulting map allows
graphical visualization of favorable and unfavorable regions of
binding within the species. The algorithm compares, pairwise,
atoms in the molecule (excluding i=j, i bonded to j, and i-x-j
1-3 interactions) for each defined grid point in the map. Thus
it usually is advisable to run this type of map calculation in
the background.
View IntraMolecular HintGrid Parameter Block
The Complementary HintGrid command calculates a projected
hydropathic map of a unknown "complementary" species based on the
structure and hydropathic species of a known species. Another
terminology would be to refer to the complementary map as a "key"
map if the known species is a receptor.
View Complementary HintGrid Parameter Block
The Difference HintGrid command allows you to add or subtract two
HintGrid maps to obtain a third grid. In the case of subtraction
the second grid is subtracted from the first. The resulting
difference grid can be used to determine regions where there is
enhanced hydropathic character if the two input maps are Molecule or
Complementary. If the two input maps are InterMolecular or
IntraMolecular maps the effects of molecular changes such as
site-directed mutagenesis (with respect to non-covalent interactions
affecting stability) between the two molecules can be examined.
Note that this algorithm requires that the two molecules have the
same orientation and that they be aligned with respect to a common
coordinate system.
View Difference HintGrid Parameter Block
The HintTable pulldown contains the commands to execute the Hint
interaction table creation for InterMolecular and IntraMolecular
interactions and for Scoring DOCK results with Hint (which is a
special case of InterMolecular HintTable).
The InterMolecular HintTable command executes the creation of a
table listing all or a subset of the atom-atom interactions
between two molecular entities. Each interaction is scored in
terms of the Hint hydropathic model. The command characterizes
each interaction and summarizes the total interaction score in
terms of interaction types.
View InterMolecular HintTable Parameter Block
The IntraMolecular HintTable command executes the creation of a
table listing all or a subset of the (1-4 and higher order)
atom-atom interactions within a molecular entity. Each interaction
is scored in terms of the Hint hydropathic model. The command
characterizes each interaction and summarizes the total interaction
score in terms of interaction types.
View IntraMolecular HintTable Parameter Block
The InterMolecular HintTable command executes the creation of a
table listing all or a subset of the atom-atom interactions
between two molecular entities. Each interaction is scored in
terms of the Hint hydropathic model. The command characterizes
each interaction and summarizes the total interaction score in
terms of interaction types.
View Ligand_Optimization HintTable Parameter Block
The Archive Functions pulldown contains the commands to operate on
Biosym Archive files sequentially, whether to analyze a dynamics
trajectory, or to characterize multiple orientations from a DOCK
run. In general these commands are similar to the analogous HintTable or HintGrid
commands that operate on only a single conformation. They require the same
Setup sequence with the addition of Setup Hint_Spreadsheet if you are planning
to use a insightII spreadsheet to record the results for Table calculations.
These functions are automated in such a way that all frames
of a Archive can be rapidly examined to create either HintTable or
HintGrid results.
The Archive Function InterMolecular Tbl command executes the creation of
tables listing all or a subset of the atom-atom interactions
between two molecular entities for each frame of an Archive file.
Each interaction is scored in
terms of the Hint hydropathic model. The command characterizes
each interaction and summarizes the total interaction score in
terms of interaction types.
View InterMolecular Tbl Archive Function Parameter Block
The Archive Function IntraMolecular Tbl command executes the creation of
tables listing all or a subset of the (1-4 and higher order)
atom-atom interactions within a molecular entity for each frame
of an Archive file. Each interaction
is scored in terms of the Hint hydropathic model. The command
characterizes each interaction and summarizes the total interaction
score in terms of interaction types.
View IntraMolecular Tbl Archive Function Parameter Block
The Archive Function InterMolecular Grd command executes the creation of
grid files displaying the atom-atom interactions
between two molecular entities for each frame of an Archive file.
Each interaction is scored on an interaction grid in
terms of the Hint hydropathic model.
View InterMolecular Grd Archive Function Parameter Block
The Archive Function IntraMolecular Grd command executes the creation of
grid files displaying all or a subset of the (1-4 and higher order)
atom-atom interactions within a molecular entity. Each interaction
is scored on an interaction grid in terms of the Hint hydropathic model.
View IntraMolecular Grd Archive Function Parameter Block
The Archive Function Molecule Grd command creates Hint hydropathic field
map of the molecules in the Archive. Regions of hydrophobicity, basicity, and
acidity can be identified.
View Molecule Grd Archive Function Parameter Block
The Archive Function Complementary Grd command calculates projected
hydropathic maps of unknown "complementary" species based on the
structure and hydropathic species of a known species in the Archive. Another
terminology would be to refer to the complementary map as a "key"
map if the known species is a receptor.
View Complementary Grd Archive Function Parameter Block
The LockSmith pulldown contains commands associated with the LockSmith
3D QSAR method. The LockSmith QSAR model is still under development.
It is provided as a part of Hint2.0I as a potential useful modeling tool
for interested users. Later versions of Hint may include enhancements
to LockSmith. In the LockSmith method 3D hydropathic maps of molecules
that are assumed to have the same type of activity and to bind at the
same receptor site are combined to produce an activity-weighted
consensus map. The relation between this LockSmith map and the component
maps/biological activities yields a form of QSAR equation relating
activity to 3D hydropathic structure that can be used to model the
activity of new, unmeasured compounds.
The basic steps in creating a LockSmith model are: 1) creating molecular
models for the collection of molecules; 2) overlapping the molecules in
some rational way that emphasizes the commonalities of pharmacophores,
etc.; 3) creating HintGrid Molecule maps for each compound; 4) Open the
LockSmith model; 5) Define the LockSmith Activity algorithm; 6) Include
molecules (and molecule maps) in the model; and 7) Close the model with
Make Model. New molecules can be evaluated with Predict.
The LockSmith Open command initiates the LockSmith program by opening a
new model or reading an existing model from disk file. In the former
case, the new model is developed by Including molecules. Preexisting
models that are read from disk files can only be used to Predict the
activity of new compounds.
View Open LockSmith Parameter Block
The Include command contains the parameters for adding a molecule
(through its HintGrid) to the developing LockSmith model. Each
included HintGrid hydropathic map must be on the same grid dimensions.
As molecules are added to the model the LockSmith activity-weighted
consensus hydropathic map is refined and a structure-activity
relationship amongst the included molecules is developed. After all
molecules have been added to the model, the Make Model command should
be executed to complete the model.
View Include LockSmith Parameter Block
The Activity command sets up the relationship between the measured
molecular activity and the functionalized activity used in the LockSmith
model. LockSmith requires that 1) molecules have nonzero activity, 2)
that "more active" molecules have activities higher than "less active"
molecules, and 3) that the dynamic range of activity be on the order of
one or two orders of magnitude.. This command generates an equation
relating measured activity to an activity scale meeting these requirements
that is termed the functionalized activity.
View Activity LockSmith Parameter Block
The LockSmith Make Model command creates a QSAR equation from the
relationship between each molecule's HintGrid map to the LockSmith
consensus map fit (least squares) to the biological activity for each
molecule. The model can then be used to Predict the activity of
molecules not included in the original learning set by comparing their
3D hydropathic structure to that of the consensus map.
View Make Model LockSmith Parameter Block
The LockSmith Predict command contains the parameters to predict the
activity of a new compound from an existing LockSmith model. The
new molecule should be aligned in a chemically meaningful way with
the molecules in the model learning set. The input to the model is
the HintGrid map of the molecule, which should be created with the
same options as the maps used to construct the model.
View Predict LockSmith Parameter Block
The LockSmith Put Model command writes the selected LockSmith activity
model to disk files. The model consists of two parts and two disk
files: 1) the LockSmith activity-weighted hydropathic consensus map of
the learning set molecules, and 2) equations relating the activities
to the 3D maps.
View Put Model LockSmith Parameter Block
The SMILES pulldown contains commands associated with Hint2.30Di. These
commands allow the use of SMILES line notation as input to the
InsightII Builder module. SMILES is briefly described in the Theory
Chapter. A complete description is in Weiniger, D. J. Chem. Inf.
Comput. Sci. 1988, 28, 31. Note that the Biosym
Sketcher license is required to create 3D molecule objects from SMILES strings.
The Edit SMILES command contains the parameters for entering a SMILES
string from the keyboard. Execution of this command creates both an
InsightII 2D SMILES object and an (undisplayed) Daylight Toolkit
molecule object. Note that the 2D SMILES object is indistinguishable
from a Sketch 2D object and can be manipulated with Sketcher commands.
To create a 3D molecule object, use the 3D Convert command in the Sketcher pulldown
of the Builder module.
View Edit SMILES Parameter Block
The Get SMILES command contains the parameters necessary to retrieve
SMILES strings from disk files. Execution of this command creates both
InsightII 2D SMILES objects and Daylight Toolkit molecule objects. Note
that a 2D SMILES object is indistinguishable from a Sketch 2D object
and can be manipulated with Sketcher commands. To create a 3D molecule
object, use the 3D Convert command in the Sketcher pulldown
of the Builder module.
View Get SMILES Parameter Block
View Get SMILES Parameter Block
The Put SMILES command contains parameters for creating and writing to
disk file 2D SMILES objects created from InsightII molecule objects.
View Put SMILES Parameter Block