Hydrophobic/philic Surfaces Panel
The Hydrophobic/philic Surfaces panel is used to generate hydrophobic and hydrophilic surface maps for a structure, which is usually a receptor-ligand complex.
To open this panel, click the Tasks button and browse to Structure Analysis → Hydrophobic/philic.
- Using
- Features
- Additional Resources
Using the Hydrophobic/philic Surfaces Panel
The generation of the surfaces 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).
To create hydrophobic and hydrophilic surfaces, you first need to import the receptor and a docked ligand and display them in the Workspace. It is suggested that you select the ligand as the set of atoms to use for the bounding box. Open the Hydrophobic/philic Surfaces panel. In the Bounding box section, click Updated from Workspace Selection. 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 below.
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.
Hydrophobic/philic Surfaces Panel Features
- Bounding box
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Select Display to display the bounding box in the Workspace (the default).
Click Update from Workspace Selection to set the size of the bounding box to just enclose the atoms that are selected in the Workspace. By default, the box is fitted to all atoms.
- Box margin text box
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The box margin is used to provide a buffer around the minimal enclosing box. To alter the box margin, change the value in this text box.
- Grid spacing option menu
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Choose from two grid spacings Standard, for faster surface generation, or Fine, for higher surface quality.
- Job toolbar
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Manage job submission and settings. See Job Toolbar for a description of this toolbar.
- Status bar
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The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.
Use the Reset button
to reset the panel to its default settings and clear any data from the panel. The status bar also contains the Help button
, which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a 
button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.
Hydrophobic/philic Surfaces Background
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: regions that are favorable for occupancy by hydrophobic ligand groups
- Hydrophilic: regions that are favorable for occupancy by hydrophilic ligand groups
- Neither hydrophobic nor hydrophilic: regions that are of mixed character or that are far enough from the receptor surface to be similar to bulk water, where to a first approximation any type of group could reside with little effect on the binding affinity.
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 default OPLS 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.