Subject: Summary: Rolling H charges into their heavy atoms?

From: [email-masked]
Date: Sun, 02 May 1999 15:46:50 -0700

I wish to extend my thanks again to those people who replied to my question! 
Their replies follow my original question below.  I greatly appreciate their
feedback.

Kenward Vaughan

In <199904262212.SM00238@kaynjay>, on 04/26/99 
   at 09:20 PM, [email-masked] said:

>Hello people,

>I wanted some opinions from those well versed in the field about a practice
>I've seen mentioned in some docking studies with proteins (an area in which
>I'm interested).  Most PDB files have no H's mapped.  Since the ESP is
>important in those studies, having some good estimate for the partial
>nuclear charges is naturally important.  It appears that one can either add
>the H's onto the existing structure or take a well-calculated amino acid
>structure (using an ab initio program) and additively "roll" the nonpolar H
>charges into their respective heavy nuclei.  In this case, those which
>might H-bond seem to be treated separately (added to the structure), which
>makes sense to me.  

>First, is this a reasonable 1st-level understanding of the approaches to
>this?  Or have I misunderstood things?

>The second approach (rolling charges into the heavy atoms) would certainly
>appear to be the easiest to adopt.  Is there good reason Not to do either
>approach?  In both I can see an issue of accuracy for a number of obvious
>reasons from the QM perspective, but wonder about the validity of this
>concern on the broad scale over which these protein interactions occur.

>Any references would also be appreciated.  My apologies if this seems
>trivial or mundane ... I'm quite new to all of this, and am learning it
>near the back of a dark cave ...  :)  Thanks very much!

and the replies:

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From: "R.M.Day" <[email-masked]>

Hi Kenward

this might be irrelevant, but your question is far from trivial and is
something we fix with MM.

XRAY crystallography cannot give you Hydrogen coordinates - hydrogen atoms
dont deflect much at all.  How this this normally got around is bythe use of
MM and with partial charges from dictionaries from the likes of Kollman et
al.. These have been found to be "good" enough for most modelling & docking
jobs. People have found that such models built this way are pretty well
realistic, proven by comparison with NMR etc.

Its only a model after all - intuition rules OK. 
[...]

Best of Luck,

Richard Day

----------------------------------------------------------------------
From: David van der Spoel <[email-masked]> 

Basically, your question boils down to: is it better to add the hydrogens or
to use a united atom approach. Obviously the charge is delocalized and
therefore it is in principle better to have more particles (the Hs) to be
able to reproduce the electronic structure better. The problem is that we do
not know the electronic structure of a protein (in a certain conformation)
with sufficient accuracy to make a fit of atomic charges that reproduces the
electrostatic potential due to the "real" electron density. Thus we use model
systems (amino-acid crystal for example) to derive atomic charges, or
ab-initio calculations on isolated amino acids.  The resulting charges (and
the rest of the force field) must then be tested for its ability to reproduce
experimental data, and then conclusions on the quality of the charges can be
drawn. It should be stated that the trend is towards all-atom force fields,
but is not always clear how well they perform.

Some (old) references:
@Article{Teleman91,
  author = 	 {O. Teleman and P. Ahlstr{\"o}m and B. J{\"o}nsson},
  title = 	 {On the use of united atoms in statistical mechanical simulations
of biomolecules},
  journal = 	 "Mol. Sim.",
  year = 	 1991,
  volume =	 7,
  pages =	 {181-194}
}
@Article{Veenstra92a,
  author = 	 {D. L. Veenstra and D. M. Ferguson and P. A. Kollman},
  title = 	 {How Transferable are Hydrogen Parameters in Molecular Mechanics
Calculations?},
  journal = 	 "J. Comp. Chem.",
  year = 	 1992,
  volume =	 8,
  pages =	 {971-978}
}
@Article{Kini92,
  author =       "R. M. Kini and H. J. Evans",
  title =        "Comparison of Protein Models Minimized by the All-Atom
                 and United Atom Models in the {AMBER} Force Field:
                 Correlation of {RMS} deviation with the
                 Crystallographic {R} Factor and Size",
  journal =      "J. Biomol. Struct. Dyn.",
  year =         "1992",
  volume =       "10",
  number =       "2",
  pages =        "265--279",
}
@Article{Kaminski94,
  author =       "George Kaminski and Erin M. Duffy and Tooru Matsui and
                 William L. Jorgensen",
  title =        "Free Energies of Hydration and Pure Liquid Properties
                 of Hydrocarbons from the {OPLS} All-Atom Model",
  journal =      BTjpc,
  year =         "1994",
  volume =       "98",
  pages =        "13077--13082",
}

Groeten, David.

----------------------------------------------------------------------
>From a later note from Dr. van der Spoel <[email-masked]>

In the united atom models one usually has the polar hydrogens (NH, OH)
present while the aliphatic hydrogens (CH) are taken out. These force fields
(GROMOS, AMBER, CHARMM, OPLS) usually give reasonable results, but you have
to check with the literature yourself. Adding explicit H to aliphatic groups
does not seem to make a big difference for proteins (which are dominated by
electrostatics) although it does for small organic molecules. Furthermore it
is now common in all force fields to have explicit hydrogens on Tyr, Phe and
Trp to reproduce quadrupole moments.

To get the electrostatic potential you use one of the force field charge sets
and a solver for the Poisson Boltzman equation (such as Delphi or MEAD). If
you would leave out the dipolar groups and only maintain the charged groups
your potential would be correct at  long distance but not close to the
protein. Actually, what would be interesting I think is to compare the ESP
calculated by different charge sets. I have a gut feeling that the results
will be fairly similar although the charges sometimes differ quite a lot...

Groeten, David.

----------------------------------------------------------------------
From: [email-masked]

Hello Kenward,

I'm new at this too. But I was reading and artcile about CHARMM and they talk
about the advantages and disadvantages of the extended-atom representation on
its third page. The artcile is very big. Here is the reference: Journal of
Computational Chemistry, Vol. 4 No. 2, 187-217 (1983). Hope it helps!

Best regards,

Fernanda

----------------------------------------------------------------------
From:  Jeffrey L. Nauss, PhD <[email-masked]>

If I understand you correctly, you are comparing a united atom vs polar
hydrogen model vs and all-atom model for molecular structures.

>First, is this a reasonable 1st-level understanding of the approaches to
>this?  Or have I misunderstood things?

I would say it is a reasonable start (assuming I understood your point). But
"rolling" hydrogens into heavy atoms also includes expanding the Van der
Waals radii as well.  This accommodates the positions of the hydrogens.

>The second approach (rolling charges into the heavy atoms) would certainly
>appear to be the easiest to adopt.  Is there good reason Not to do either
>approach?

Early molecular mechanics force fields (Amber and Charmm) were united or
polar hydrogen models.  The reasons for doing so were many including the lack
of computer power 10-20 years ago.  Modern force fields (Amber Cornell and
Charmm 22) use all atom representations as they are more accurate in terms of
intermolecular interactions.  However, these modern force fields also work
better with explicit solvent.

For small molecules, my understanding is that you need an all-atom
representation to get any decent results at all. 

>Any references would also be appreciated. 

You might try these and references therein:

1.  MacKerell Jr., A. D., Wiorkiewicz-Kuczera, J., Karplus, M. 1995. An
all-atom empirical energy function for the simulation of nucleic acids. J.
Am. Chem. Soc. 117:11946-75

2.  Cornell, W. D., Cieplak, P., Bayly, C. L., Gould, I. R., Merz, K. M.,Jr.,
et al. 1995. A Second Generation Force Field for the Simulation of Proteins,
Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 117:5179-97

3.  MacKerell, A. D., Jr., Bashford, D., Bellott, M., Dunbrack, R. L., Jr.,
Evanseck, J. D., et al. 1998. All-atom empirical potential for molecular
modeling and dynamics studies of proteins. J. Phys. Chem. B 102:3586-3616

4.  Weiner, S. J., Kollman, P. A., Nguyen, D. T., Case, D. A. 1986. An All
Atom Force Field for Simulations of Proteins and Nucleic Acids. J. Comp.
Chem. 7:230-52

----------------------------------------------------------------------
And in a later letter from Dr. Nauss ...

[...] if you look at Barry Honig's DelPhi, he uses only formal charges on
ionizable side chains.  He completely ignores partial charges on neutral side
chains and the backbone.  I have yet to see (or to do myself) comparisons of
different charge sets.

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[email-masked]
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