6. How can I substitute inhibitors or do docking?

Let's assume that for your substitution you want to place the new inhibitor in the same place as the old one. You can do this by using the draw tool to make the minimum changes needed to change the old inhibitor to the new inhibitor. You can then select only the changed parts and model build (the unselected atoms will keep the same coordinates).

If you are interested in semi-empirical calculations you could then start modelling.

For molecular mechanics simulations you would first need to set the atom types and partial charges of the new inhibitor (you don't need charges for MM+ if you are using bond dipoles for non-bonded electrostatics). The types can be set by selecting the inhibitor and using Build/Calculate Types (checking that none are ** unless you are using MM+). The charges are trickier--you could enter "standard" values manually if have them, select the inhibitor and use ChemPlus QSAR Properties to calculate partial charges, or isolate the inhibitor and use a semi-empirical calculation.

A feature that you might wish to use, particularly to "isolate the inhibitor" for charge calculations, is File/Merge once you have set it to not translate the merged-in molecule. By default, File/Merge and Edit/Paste translate the added part (in the viewer's X direction) so that it does not overlap with the current system. You can turn off this behaviour via a HyperChem script command. Perhaps the simplest way to do this is to use Script/Open Script to read in a text file that consists of the script command:

translate-merged-systems no

If you always want this behaviour, put this command in a CHEM.SCR file (in your ChemIniPath) so that the command is executed whenever you start HyperChem.

Once you have turned off translate-merged-systems, you can save, delete and merge to work with parts of the system independently without losing relative position information. For instance, to get charges after model building the changed portions of the inhibitor, you could:

1. Save the total system, eg. as both.hin.

2. Select and cut (via Edit/Cut) the inhibitor, then save as protein.hin.

3. Use Edit/Paste, Select/Complement Selection, Edit/Delete and then save as inhibit.hin.

4. Now use a semi-empirical calculation (single point or optimization) to calculate charges (and perhaps a better geometry).

5. It's probably a good idea to save, perhaps overwriting inhibit.hin.

6. Use File/Merge to read protein.hin and save, perhaps overwriting both.hin.

Now you should have a reasonable starting point for molecular mechanics calculations of the new inhibitor and the protein.

When you don't already have an inhibitor or substrate to replace, HyperChem allows two methods of "docking" a small molecule (substrate) onto a larger molecule (receptor). These are manual docking, and restrained energy minimization.

Manual docking is carried out purely through moving molecules around on the screen: no actual simulation is carried out. Any "docked" structure obtained in this way should then be optimized to remove bad contacts and other unrealistic aspects of the structure.

Restrained minimization requires a docking hypothesis (atom A on the substrate is assumed to be close to atom B on the receptor) which is incorporated into a simulation using restraints. A combination of dynamics and optimization subject to these restraints allows you to force proximity of substrate and receptor atoms. After restrained optimization you can turn off the restraints and use further optimization and dynamics to test the docking hypothesis. If you select only the substrate to freeze the receptor, you may prefer to use one-atom restraints to tether substrate atoms to points in space that you define to be in your proposed docking site.

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