Re: [AMBER-Developers] sqm success/failure on ANP

From: Ross Walker <ross.rosswalker.co.uk>
Date: Thu, 20 Jan 2011 12:28:59 -0800

Hi Eric,

Just to add my comments to this discussion.

> Thanks for looking into this. I have noticed that many sqm SCF
> failures occur with ligands that include phosphate groups, which is in
> line with your observation of SCF convergence difficulties with highly
> negatively charged structures.
> The ANP structure in the context of the 2ews PDB entry doesn't
> really
> allow for the "optimized" geometry delivered by mopac with it's
> internal H-bonds to the phosphates, since in 2ews those phosphates are
> occupied by H-bonding to the protein backbone and coordinating a
> magnesium ion. Unfortunately sqm couldn't possibly run on ANP in the
> larger context of the entire 2ews system, where the negative phosphate
> charges would be stabilized by ANP's environment. Maybe if the
> magnesium ion had been included in the sqm input (with the appropriate
> formal charge change) it would have worked?
> Anyway, here's hoping for a trickier sqm sometime in the future!
:-)

I would suggest that you take a step back for a second and consider what you
are actually asking for here. You are running the ligand in gas phase and
yet somehow suggesting that you actually want the behavior in the protein
but you do not want to include the protein. Unfortunately to quote an
overused saying, there is no such thing as a free lunch. What you are
attempting to do, particularly with phosphates, is notoriously hard. I would
suggest going back to the drawing board and considering how you might run
the calculations you want with the steric environment of the protein somehow
included. What you have is certainly a problem case and you will not be able
to treat it in a simple na´ve fashion. Chances are you have significant
electronic exchange with the protein which makes it unreasonable to consider
the charged phosphate system as it is in isolation. You are probably well
outside the scope of semi-empirical so I would suggest considering something
more rigorous such as an ab initio approach. Certainly it is probably
unreasonable to assume that simple AM1-BCC can be applied to complex highly
charged systems like phosphates.

Think about how you might be able to include the protein environment in the
calculation. Possibly fixing the geometry of the surrounding residues and
capping them in a consistent fashion, for example with ACE and NME caps.
Whatever you end up doing you will need to be consistent and be prepared to
defend the choices you made under review. You may also want to carefully
check the literature to see what people have done in the past for similar
systems.

I am sorry if this is not the answer you wanted but I think you are well
outside of what Antechamber / SQM are capable of handling in an automated
fashion.

All the best
Ross

/\
\/
|\oss Walker

---------------------------------------------------------
| Assistant Research Professor |
| San Diego Supercomputer Center |
| Adjunct Assistant Professor |
| Dept. of Chemistry and Biochemistry |
| University of California San Diego |
| NVIDIA Fellow |
| http://www.rosswalker.co.uk | http://www.wmd-lab.org/ |
| Tel: +1 858 822 0854 | EMail:- ross.rosswalker.co.uk |
---------------------------------------------------------

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Received on Thu Jan 20 2011 - 12:30:02 PST
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