CHARMM Development Project Forums User Discussion & Questions Parameter Set Discussion Saving in mol2 format for paramchem, using DS 2.5

I wanted to follow up on a previous post in which I asked about how to save molecules in mol2 format for submission to the paramchem.org for automated atom typing and parameter assignment for the cgenFF.

This was very straightforward using Accelerys' Discovery Studio 2.5 (a successor to their Insight II software, I believe, so I imagine this should be similarly straightforward using that program as well).

Here are the steps I followed, after opening Discovery Studio. (I suspect that, e.g., existing files in non-pdb formats would work well too, but I haven't tried.)

1. Open pdb file of molecule of interest. (Mine was a pdb, previously edited for charmm use, of just my ligand of interest.)

2. Adjust charge states if necessary. (To find out charges, select Structure --> Labels --> Add, and then choose Object --> Atom / Attribute --> Formal Charge / --> OK. To adjust charge, select Chemistry --> Charge --> {+1 or -1 or Set}.)

3. Check hybridization states of molecule's atoms.

4. Add hydrogens. Chemistry --> Hydrogens --> Add

5. Check that an appropriate number of hydrogens were added to each atom.

6. Choose "Save As..." from the File menu.

7. Select "Sybyl MOL2 Files (*.mol2)" from the "Files of Type" drop-down menu, under the filename input box.

8. Choose appropriate name and directory for saving.

This produced a file with correct SYBYL atom types. Submission to paramchem was successful.

NOTE: It appears that the charge of a heteroatom can be altered after hydrogens are added, and an appropriate adjustment in the number of hydrogens will be made automatically.

This indeed looks like an appropriate procedure to follow, except that I wish to stress once again that small molecules in protein X-ray structures very often contain errors. Using software to add hydrogens and convert to mol2 often fails to yield a correct structure; in these cases, it is required to look up the primary literature and manually construct the correct ligand in a molecular editor (bearing in mind the protonation and tautomeric states, as documented in Ascaris' post).

Just for the reference of other users dropping into this thread, all the steps in Ascaris' post are very basic and can be performed using other proprietary softwares, such as Sybyl, MOE, Maestro (Schrödinger; free for academics), (probably) DS Visualizer (Accelrys; free for all), ChemBio3D,... and probably some free and open source softwares as well.

However, as mentioned in my previous post, it is often better to manually build a molecule with hydrogens in your favorite molecular editor (ie. any of the above and many more), so that you're sure you have the right molecule, right bond orders, right tautomer,... - do not blindly trust small molecules in protein X-ray structures.

Yet another note to whoever stumbles across this thread: feel free to post your experiences with performing this procedure using other programs than DS. In particular, it would be nice if the procedure could be replicated using free software.

Certainly, I should have added that confirming that the hydrogens were placed correctly by comparing the generated structure with primary literature is a *vitally important* step.

As it turns out, I was using Discovery Studio Visualizer. So, my procedure applies to that program.

Also, I should note that formal charges do not appear to be displayed unless they are nonzero (at least when following my instructions).