If you did multiple Partition calculations in Lesson 1, there are probably several molecule objects currently defined and displayed by SYBYL. This lesson is specific to the COCAINE molecule which is probably displayed in M1, but any of the molecules suggested in Lesson 1 are applicable. To delete a molecule, pulldown Build/Edit to the Zap (Delete) Molecule command; select the Molecular area associated with for each molecule that you wish to Zap.

From the eslc pulldown on the SYBYL menubar, select Hint followed by HintMap and Molecule.... This command sets up and executes calculation of a molecular hydropathic density map with the aid of the Map Molecule dialog box. First choose the Molecule..., identified by (only) its molecular area (M1 for COCAINE). IMPORTANT: HINT assumes that the molecule in area M1 at this point is the same one that was there when the contents of the molecular area were last partitioned. All data passed between SYBYL and HINT is through disk scratch files; there is no "memory" of previous transactions maintained by either SYBYL or HINT other than these scratch files.

Next, define the three dimensional extents of the map region by pressing the Region Definition... button to call the Region Definition dialog box. For this type of calculation, pick the Molecule Extents radio button from the Region menu. Choose Molecule... to be M1 (COCAINE). Margin represents a border space to be placed around the region box defined by the molecule to allow adequate field decay. A value of 5.00 is normally used. Grid Resolution is the spacing between grid points in Angstroms; use a value of 1.00. Press OK to initiate the Region Definition calculation.

From Grid Types select Hydrophobic/Polar to request a map where positive field values represent hydrophobic regions of space, and negative field values represent polar (hydrophilic) regions of space. The other option in Grid Types, Acid/Base, requests a map where Acidic and Polar regions of space are coded with positive field values, Basic and Polar regions of space are coded with negative field values, and Hydrophobic regions of space are set to zero.

Next, set the HINT Distance Function.... The Distance Function dialog box sets the two parts of the function: the Hydropathic Term and the Steric Term. For a HintMap Molecule calculation select exp(-nr) for the Hydropathic Term and set the Steric Term to off. You will use the Steric Term (van der Waals) in HINT interaction grid calculations. See the Theory chapter for a discussion of the Hydropathy distance functions used by HINT.

The Cut Off Radius serves to reduce calculation time by not considering atoms farther away than this value from the grid points during the map construction. Enter a value of 6.0 for this parameter. Volume Averaging produces a smoother map by calculating eight density values for each grid point, and then averaging them. The main disadvantage is loss of calculation speed. Set this parameter to off. The Inside Mol Cut Off allows you to set a constant value for any grid point that is within the molecular van der Waals surface. Set this parameter to off. Lastly, choose the Map File name for the SYBYL contour file to contain the map field values. Use cocaine.cnt. Now that everything is set for this map calculation, press OK to initiate it. (This calculation is quite fast; there is no advantage to running it in batch.)

The last step is to contour the HintMap for display. The Map Contour dialog box is automatically called at the completion of a HintMap calculation that is run interactively. This dialog box allows you to select the desired contour levels, their colors, and styles. The Contour File text field should be filled with cocaine.cnt, the Map File name chosen in the Map Molecule dialog box. First choose the Display Area as D1 and a Style appropriate for your display device (Lines and Dots will always work, but Opaque and Transparent require higher than minimum level graphics devices).

First contour the Polar portion of the COCAINE map. Enter a value of -7 for the first Contour Value. From the Contour Color option menu pick Red. We suggest red contours to represent Polar hydropathy. Now press the Accept button to define the first contour set. Next contour the Hydrophobic portion of the map. Enter a value of 3 for the Contour Value and pick Green for the Contour Color, press Accept. The Number of Defined Levels should now be 2. Select the Done button to contour the HintMap. The contouring calculation should take only a few seconds; a red contour surrounding the Polar portion of the cocaine molecule and a green contour surrounding the Hydrophobic portion of the molecule should appear.

HINT hydropathic map of cocaine

The contour levels suggested are only guidelines for representation of the relative contributions of Polar and Hydrophobic effects. For balance in visualization it is usually desirable to contour the Polar (-) effect at a level that is 2-5 times that of the Hydrophobic (+) effect. Keep in mind that the most hydrophobic atoms (or Leo fragments) have a[i] (or f[i]) values on the order of +1.0, while the most polar atoms (or fragments) can have values of -5.0. Hydrophobicity is a much more subtle effect than the Coulombic type effects encoded by the Polar portion of the HintMap field.

Now we will create another contour map that will help us distinguish the Acid and Base components of cocaine. Repeat the contour calculation described under #2 above . All of the settings are the same except, select Acid/Base from Grid Types to request a map where positive field values represent the Lewis Acid and negative field values represent the Lewis Base, and select cocaine_ab.cnt as the Contour File text field. After selecting OK to run the contour calculation interactively we will create a new display to distinguish the hydrophilic Lewis acid from base. After selecting OK to the Message window, the Map Contour pops up with cocaine_ab.cnt already loaded as the Contour File. First lets turn off the display of the hydrophobic/polar contour, by obtaining the Display Area Options checkbox (checkbox icon on side menu), and click On/Off under the Bkg Display for area D1. Now back to the Map Contour window, choose the Display Area as D2 and a Style appropriate for your display device. Contour the Lewis Acid blue by entering a value of 10 for the first Contour Value and picking Blue from the Contour Color option menu. Now press the Accept button to define the first contour set. Next contour the Lewis Base red by entering a Contour Value of -10 and pick Red for the Contour Color, press Accept. The Number of Defined Levels should now be 2. Select the Done button to contour the HintMap. You will see a red contour surrounding the ammonium hydrogen of the cocaine molecule and blue contours surrounding the carbonyl portions of the molecule. You can enhance your understanding of this effect by examining the atomic charges (select View, Label, Charges. Note that while you might expect a negative field near the carbonyl oxygen, the field is integrated over space and the carbonyl carbon is more positively charged. You see a similar effect around the amine. You can now compare the maps by going back to the Display Area Options checkbox and turning on and off the D1 Background Display.

HINT hydropathic map of cocaine