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Hydrophobic/philic Surfaces Panel |
The Hydrophobic/philic Surfaces panel is used to generate hydrophobic and hydrophilic surface maps for a structure.
The generation of the Hydrophobic/philic surface requires the definition of a Bounding Box within which values to be used for surface interpolation are to be computed. This is done by selecting a set of atoms, together with a "buffer distance" ( Bounding Box); the grid will be computed within the minimal enclosing box (following the coordinate axes) and extended out past each face the distance of the buffer (bounding box).
The surface generation is run as a job. Later, when the job has finished, you can monitor the job to see the results.
To open the Hydrophobic/philic Surfaces panel, you can:
Choose Workspace → Surface → Hydrophobic/philic in the main window.
To create hydrophobic and hydrophilic surfaces, you first need to import the receptor and a docked ligand and display them in the Workspace. Next, open the Hydrophobic/philic Surfaces panel. Pick an atom in the receptor to define the Part of structure to map, then in the Bounding box section, select an object from the Pick menu and pick an atom in the ligand. An orange-colored box is placed around the ligand. Click Run to run the job.
The job should take a few minutes. When it is finished, the grids are automatically incorporated into your Maestro session and the hydrophilic and hydrophobic maps appear in the Workspace, contoured at the default values of −6 and −0.5 kcal/mol, respectively, and colored turquoise and orange. You can use the Surfaces panel to change these attributes, and should use it to increase the transparency from the default setting of 0 ("opaque", which means that you won't be able to see any ligand atoms that lie within contoured regions) to ~50. You may find it more helpful to change the surface type to Mesh; this is the representation used in the J. Med. Chem. article cited above.
You may also need to change the hydrophilic and/or hydrophobic isosurface contour defaults of −6 and −0.5 kcal/mol. It stands to reason that a given location in the active site cannot be both hydrophilic and hydrophobic. Thus, the hydrophilic and hydrophobic maps should not interpenetrate, but rather should be separated by some "neither" space. This normally happens, but we are aware of at least one case in which some interpenetration occurs when the default isosurface values are used. You may need to change the isosurface values manually, possibly by setting the hydrophobic value to −0.6 or −0.7 kcal/mol. You can also make the hydrophilic value more negative than −6 kcal/mol, but should not make the definition so restrictive that important hydrogen-bonding regions are missed.
The standard picking controls in the Part of structure to map section are used to specify the part of the structure to be mapped.
Selected atoms must be contained in one and only one project entry. Selected atoms cannot be part of the Scratch Entry.
The standard picking controls in the Bounding box section are used to specify the bounding box for the Hydrophobic/philic calculation.
Selected atoms must be contained in one and only one project entry. Selected atoms cannot be part of the Scratch Entry.
The box margin is used to provide a buffer around the minimal enclosing box. To alter the box margin, enter a different value into the Box margin text box.
You can choose from two grid spacings Standard, for faster surface generation, or Fine, for higher surface quality.
The Job toolbar is used to make settings for a job and to start it.
Enter a name for the job in this text box.
This button opens the Job Settings dialog box. The arrow to the right opens a menu, from which you can make settings or perform actions that are related to the job.
The menu items are described below.
This icon indicates when there are jobs running for the application that belong to the current project. It starts spinning when the first job starts, and stops when there are no more jobs running. If a job fails to start, it changes to an exclamation point.
Clicking the button shows a small job status window that lists the job name and status for all active jobs submitted from the current panel (for Jaguar and MacroModel this means all jobs from any of the application panels). You can double-click on a row to open the Monitor panel and monitor the job, or click the Monitor button to open the Monitor panel and close the job status window. The job status is updated while the window is open. If a job finishes while the window is open, the job remains displayed but with the new status. The rows are colored according to the status: yellow for submitted, green for launched, running, or finished, red for incorporated, died, or killed. Click anywhere outside the window to close it.
Run the job with the current job settings.
The status bar displays information about the current job settings for the panel. This includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. It also displays a message for a short time when you start a new job.
The status bar also contains the Help button, which opens the help topic for the panel.
The Hydrophobic/philic map tool is a 3D graphics tool that is designed to assist in visualizing preferred locations of ligand atoms in a receptor site. Given a receptor structure, the accessible space in the active site is partitioned into three types of regions:
Hydrophobic and hydrophilic regions are marked by surface contours that enclose the region in question. The "neither" regions, in contrast, are implicit; these are simply regions that are accessible to the ligand but are not marked as being either hydrophobic or hydrophilic.
By revealing "targets of opportunity" - e.g., hydrophobic regions that have room to accommodate a larger hydrophobic group - active site maps can aid in the design of new ligands. Alternatively, by showing the degree to which poses produced by a program like Glide display -or violate - proper complementarity to the receptor site, site maps can aid in the evaluation of docking hits. The "neither" regions are also important because they are regions in which the physical properties of the ligand can be changed - for example, to make the ligand more or less soluble - with minimal expected effect on the binding affinity.
The active-site mapping procedure operates in a manner analogous to Goodford's GRID algorithm (P. Goodford, J. Med. Chem. 1985, 28, 849). "Hydrophilic" and "hydrophobic" regions are defined in a way that considers both spatial proximity to the receptor and suitability for occupancy by solvent water. A putative van der Waals energy and the magnitude and direction of the electric field (calculated using a distance-dependent dielectric formulation) are computed for a probe centered at each grid point by considering interactions with all atoms of the receptor site within a defined cutoff distance. In contrast to techniques that color-code the receptor surface to represent hydrophilicity or hydrophobicity, site maps depend on more than the character of the nearest receptor atom. Moreover, site maps explicitly show the shape and extent of hydrophilic and hydrophobic regions, something a receptor-surface display cannot do. The site maps behave rather like an "extraradius" surface in that the atoms of a stick figure representation of the ligand can approach but should not penetrate the site map surface (except in hydrogen bonding regions, where internuclear distances are expected to be smaller than normal contact vdW distances).
Hydrophilic Map: a measure of "hydrophilicity" is constructed by adding an "electric-field reward" term to the vdW energy (Equation 1):
Grid_philic = vdW_energy + oriented-dipole_energy (1)
where the oriented-dipole energy is necessarily negative. Hydrophilic regions then are those within which the sum of the two terms is sufficiently negative, and are revealed by contouring the "hydrophilic grid" at a prescribed negative isosurface value, typically -6 kcal/mol.
Hydrophobic Map: Conversely, the quantity representing "hydrophobicity" is constructed by adding an oppositely signed (positive) "electric-field penalty" term to the vdW term (Equation 2):
Grid_phobic = vdW_energy − 0.15 oriented-dipole_energy (2)
Hydrophobic regions thus are taken to be those for which the favorable vdW term is not too strongly degraded by the positive electric-field penalty. Qualitatively, therefore, hydrophobic regions are those that lie suitably close to the surface of the receptor but for which the water-dipole-orienting electric field produced by the receptor is sufficiently small. In short, these are regions where something would like to be, but water would not. Hydrophobic regions are revealed by contouring the associated grid at a suitably negative threshold, e.g., −0.5 kcal/mol. The hydrophobic regions for human renin defined in this way are illustrated in the stereo pair shown in Figure 3 of Weber, Halgren, et al., J. Med. Chem. 1991, 34, 2692-2701.
Method: The first step in computing grids is to define a rectilinear box that contains an active site and to define grid points with a typical grid spacing of 1 Å within the box. Next, van der Waals energies and x, y, z electrostatic field components are computed at each of the grid points. Receptor atom partial charges and van der Waals parameters are taken from the OPLS-AA force field. A probe is represented by a van der Waals sphere of radius 1.5 Å and well depth 0.2 kcal/mol, and has a point dipole moment of 2.3 debye. The probe's point dipole is oriented along the electric field to give a minimum (negative) electrostatic energy and is offset from the vdW body (which is located at the grid point and represents the oxygen atom of a water molecule) toward the center of an optimally oriented O–H bond. A smoothing procedure is applied during the calculation of the receptor's electric field to avoid artificial singularities. The "hydrophilic" and "hydrophobic" grid values are then determined from Equations 1 and 2. Finally, the hydrophilic and hydrophobic grids are read by Maestro, which contours the grids at the empirically selected default isosurface values cited above (−6 and −0.5 kcal/mol) and displays the corresponding hydrophilic and hydrophobic volumes as solid/translucent or wire-frame surfaces. These values can be changed in the Maestro Surfaces panel if more expansive or more restrictive hydrophilic and hydrophobic volumes are judged to be appropriate in a given application. Because you need to see inside these surfaces, you may find that the hydrophilic and hydrophobic volumes are easier to visualize if you display them as mesh surfaces. If you display them as solid surfaces (the default in Maestro 5), you will need to increase the transparency by moving the Transparency slider about half way to the right.
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