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

From: Eric Pettersen <pett.cgl.ucsf.edu>
Date: Thu, 20 Jan 2011 14:35:13 -0800

Hi Ross,
        Your points are well taken. If my usage scenario were that of a
researcher doing an in-depth analysis of the 2ews system I would
certainly hope to carry out the kinds of sophisticated calculations
you outline, but that's not my usage scenario. As a developer of
Chimera I need to use antechamber/sqm to assign not-unreasonable
partial charges to these kinds of molecules so that systems can be
prepared in a semi-automated fashion for docking runs or written out
as prmtop files or used directly in Chimera's minimizer (which
currently used MMTK but for which we hope to develop a Python
interface to Amber's SFF routines soon), etc.
        My hope, of course, is that something is better than nothing, at
least for the kind of users that could not possibly hope to carry out
ab initio calculations to get a more exact answer without at least
many additional months of effort. And of course for certain kinds of
bulk calculations such an approach is infeasible anyway.
        If it turns out that sqm simply cannot perform the charge computation
on something like an ionized ATP molecule then I may have to use
"charge templates" for such molecules as much as possible, like
Chimera already does for amino/nucleic acids and water. Perhaps using
values from the "AMBER parameter database" (http://www.pharmacy.manchester.ac.uk/bryce/amber
) or some such. Maybe I should do the latter anyway for ionized ATP/
ADP/GTP/GDP (which is the only form in the database) -- any opinion on
whether the database charges are comparable or better than the
corresponding (successful) sqm computation?

--Eric

On Jan 20, 2011, at 12:28 PM, Ross Walker wrote:

> 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 - 15:00:04 PST
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