The antechamber program is a helpful tool for ligand (i.e. drug and inhibitor) parametrization, assuming you have a pretty typical organic molecule. (If not, you’ll need to do this the Gaussian way, or the REDD way.) First, make a PDB file with only the ligand molecule–no protein, no metal, just ligand. If your ligand is in the PDB with everything else, copy the lines with the ligand into a new PDB file. If your ligand PDB does not have hydrogens, then those will need to be added. Luckily, AMBER’s reduce program can do this!

$AMBERHOME/bin/reduce ligand_missing_H.pdb > ligand_with_H.pdb

Amazing, now you should have hydrogens where they need to be. Now you’re ready to use antechamber, which may take a little bit of time depending on the size of your ligand, because AMBER will be running a quantum calculation.

$AMBERHOME/bin/antechamber -i ligand_with_H.pdb -fi pdb -o ligand_with_H.mol2 -fo mol2 -c bcc -s 2 -nc 0 -m 1

So, what the fruitcakes did that all mean? First, you’re reading in the PDB file (and saying that your file in is a PDB), telling it what file to write out (and saying that your file out is a mol2 file). The -s 2 tells the program to be verbose, so that all of the information is printed to the Terminal (it’s helpful for debugging this command). The -c bcc specifies what type of quantum calculation you’re running–in this case, it’s AM1-BCC (Austin Model 1-Bond Charge Corrections). It’s not meant to be super great–it’s a quick and dirty calculation, because you’re likely doing this same parametrization for a great number of compounds. If you really care about this ligand’s parametrization, then you’ll want to consider using RESP charges (and now we’re back to the RESP ESP charge DData Base Home Page). There are other charge options for antechamber, too, which can be found by doing antechamber -L. Anyway, the -nc 0 says that the net charge is zero. If your ligand has a +3 overall charge, use -nc 3; for a -2 overall charge you’d use -nc -2. If you’re lazy and guess 0 when there’s really a charge, you’ll probably get an error at this step–though you really should take the 20 seconds to determine if there’s a charge. Finally, the -m 1 specifies the multiplicity of the ligand. This is determined through 2S + 1, where S is the total number of unpaired electrons in the system. Thus, with zero unpaired electrons, this is 1.

Hooray, we’ve made it through the antechamber step, which gave us a ligand with charges in a mol2 file. With that information, we can use parmchk to make a force field modification file (known as an frcmod) for the ligand.

$AMBERHOME/bin/parmchk -i ligand_with_H.mol2 -f mol2 -o ligand_with_H.frcmod

Great! That’s done! You now have an frcmod file that has parameters specific to your ligand based on the Generalized Amber Force Field (GAFF) for organic molecules. You’re now ready to move onto LEaP.