Subject: Summary: S-charges

From: "E.E.Moret" <[email-masked]>
Date: Tue, 5 Jul 94 23:34:34 METDST

Dear colleagues,

Thanks to all who responded so helpfully to my question on sensible
S-charges. Some replies indicated even higher S-charges, than the ones
I calculated semi-empirically. These results were obtained on quite
different compounds, however. Some colleagues computed the charges on
my model compound with 6-31++G** and also DFT methods. I intend to use
these charges, that are close to +1 for the S-atom. For the bioactive
molecules we are studying, I will change the semi-empirical charges
only on the sulfonamide-moiety accordingly and leave the rest of
the molecules (peptides) as computed. A colleague in Leiden is currently
working on the ab initio stuff. Like with Mopac-ESP, CHELPG gives
charges comparable to Mulliken with 6-31G* basis sets, according to the
calculations from Dr. Guadagnini. As his reply shows, however, the CHELPG
6-31++G** S-charge is only +0.5 !!
Some references on the derivation of S-charge for force-fields are highly
appreciated.

Thanks again. The original messages and the replies are appended. I did
not include a Dutch reply, offering me a recent CSD-search which would
enable me to check the geometry statistics.

With best regards,
Ed Moret

**************************
From: "E.E.Moret" <[email-masked]>
Subject: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?
Date: Sun, 26 Jun 94 13:41:40 METDST

Dear colleagues,

A good scientific discussion is appropriate and let me be the first to
say that I am aware of the fact that my subject line is questionable.
There is no right or wrong charge. Atomic point charges are merely a useful
concept in computational chemistry. However, the semi-empirical charges
I have obtained for the hypervalent S atom are a problem. They disrupt
molecular mechanics calculations that I want to perform. I face the
problem of accepting these charges or considering them useless for
my purpose (docking). Here is my dilemma:

We are currently studying molecules with around 100 atoms of which
a sulfonamide group is of relevance. Apart from a geometry that does not 
correpond to X-ray and ab initio information, we observe large positive
charges on the S atoms. 
Some calculation results on the molecule CH3-SO2-NH-CH3 follow.
The C-S-N-C torsion angle in the input file was close to the
ab initio and X-ray data of 70 or -70.

I used MINDO3,MNDO,AM1,PM3 Hamiltonians in Ampac 2.1, Mopac 5, Mopac 6 and 
Mopac 93. The partial charge on the S atom varied between 1.6 and 2.6 !
Fortunately, there was no programme dependency, apart from programmes that
explicitly mentioned the use of a different Hamiltonian for one element.

This would be a typical result for the S-charge (Mopac93):

sulfa_opt_MINDO3:        6          S           1.849085     
sulfa_opt_MNDO:          6          S           1.632472      
sulfa_opt_AM1:           6          S           2.526724    
sulfa_opt_PM3:           6          S           2.159568       

The input-file with cartesian coordinates is appended at the bottom.
Besides interesting geometry and charge, the bond orders for the bonds from
S to C or N are typically 0.7, whereas the bond orders for the bonds
from S to O are 1.15.

I consider the system size prohibitive for ab initio calculations and I hesitate
to use an empirical charge calculation. I would value your input
on the following questions:
- am I wrong in considering the current results conspicuous?
- should I accept the current charges, geometry and bond orders?
- should I turn to more rigorous or more empirical methods?
- should I fiddle the current charges (i.e. changing the S valency by hand and
substracting some pos. charge of S and some neg. charge of its neighbouring
atoms, which would be a manual reduction?
- are their experimental data which would allow me to check whether the current
results predict the right interaction or behaviour of S-containing compounds.
- will the P atom give comparable results?

For those who noticed that I avoided naming P and S. Is it a phosphorus atom and
a sulphurous atom or is sulphur and phospor correct english?

I am looking forward to your ideas on this topic.

AM1 T=3600 NOINTER PRECISE BONDS 
./sulfa_opt_AM1.dat
 
0001 0.0000    0000 0.0000    0000 0.0000    0000 0000 0000 0000
0001 1.7964    0000 0.0000    0000 0.0000    0000 0000 0000 0000
0001 1.4572    0000 3.3222    0000 0.0000    0000 0000 0000 0000
0001 3.5945    0000 3.7754    0000 0.5259    0000 0000 0000 0000
0006 0.8982    0000 0.1420    0000 0.6190    0000 0000 0000 0000
0016 0.8981    0000 1.7989    0000 1.3224    0000 0000 0000 0000
0007 1.6790    0000 3.0433    0000 1.0195    0000 0000 0000 0000
0006 3.1526    0000 2.9846    0000 1.1500    0000 0000 0000 0000
0001 0.8982    0000 -0.5819   0000 1.4472    0000 0000 0000 0000
0001 3.5287    0000 2.0089    0000 0.8086    0000 0000 0000 0000
0001 3.4511    0000 3.1472    0000 2.1961    0000 0000 0000 0000
0008 0.4152    0000 1.4318    0000 2.6394    0000 0000 0000 0000
0008 -0.3714   0000 2.2528    0000 0.7887    0000 0000 0000 0000

From: "E.E.Moret" <[email-masked]>
Subject: CCL:Semi-empirical S-charges II
Date: Mon, 27 Jun 94 13:35:16 METDST

Dear colleagues,

With regards to the question about 'sensible' charges on sulfur atoms:

The first responses to my question have arrived (thanks) and suggest to me
that I need to clarify 2 things:

- the CH3-SO2-NH-CH3 is only a test model for the sulfonamide containing
bioactive compounds with approximately 100 atoms. Large basis set ab initio
calculations could only be applied to part of the molecules.
- Potential derived charges may be the best for modelling purposes and they
may be less basis set dependent. Is this correct, even if the basis set
lacks incorporation of d-orbitals?
I calculated the ESP (Bessler, Merz, Kollman) charges with Mopac93:

Molecule Ch3-SO2-nh-ch3 (important atoms in capital letters):

Atom          Mulliken        ESP
C             -0.82           -0.99
S              2.53            2.45
N             -0.78           -0.96
O             -0.84           -0.78
O             -0.91           -0.88
**************************

Date: Sun, 26 Jun 94 13:36:22 -0400
From: [email-masked] (Randy Boehm)
Subject: charges_reply

The best (arguably) way to get partial atomic charges is to do a
fit to the electrostatic potential.  I have done such calculations and
have found that S in SO4 is about +3.   I your MM applications can not
handle such values, then get a differenct or develop your own.
**************************

Date: Sun, 26 Jun 94 13:02:45 -0700
From: [email-masked] (Marvin Waldman)
Subject: Sulfur charges

It is indeed an interesting question as to what is the appropriate
charge for a hypervalent sulfur attached to so many electronegative
atoms (2 oxygens and a nitrogen).  My two suggestions are to see
what kinds of charges you can get by fitting to electrostatic
potentials, as opposed to the Mulliken charges which are the ones
I assume you are reporting.  Options for calculating ESP-fitted
charges are available in the more recent versions of Ampac and Mopac.
Alternatively, can you perform some ab initio calculations
(need to be at least at 6-31G* - maybe higher) on a small model
compound such as CH3-SO2-NH2 to see what kind of charge is found
on the sulfur?

I would be interested in seeing the results of any further analysis
or prior work that you uncover on this topic posted back to the net.
**************************

From: Dan Severance <[email-masked]>
Subject: Re: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?
Date: Sun, 26 Jun 94 16:06:46 EDT

      I don't know if it's an option in MOPAC 93, but try electrostatic
   potential fit charges; they are MUCH less sensitive to basis set used
   than Mulliken charges.

From: Dan Severance <[email-masked]>
Subject: Re: CCL:Semi-empirical S-charges II
Date: Mon, 27 Jun 94 11:38:03 EDT

> - Potential derived charges may be the best for modelling purposes and they
> may be less basis set dependent. Is this correct, even if the basis set
> lacks incorporation of d-orbitals?
> I calculated the ESP (Bessler, Merz, Kollman) charges with Mopac93:
> 
    Compute the ESP with all 5 basis sets and compare; they are going
  to be different than the Mulliken charges (in general).  We've had
  surprisingly good luck using CHELPG charges out of G92
  (POP=CHELPG,DIPOLE) which constrains the dipole moment to be correct.
  G92 does have all of the semi empirical basis sets built in to it as
  well.
    The other option is to do ab initio (POP=CHELPG or your favorite
  ESP fit) on this piece just to check the charges for this test
  molecule.  You can always derive the charges on a "per residue" basis
  approximating that the other pieces of the molecule have a minimal
  effect on the charges.
**************************

Date: Mon, 27 Jun 94 09:34:39 EST
From: Dr. Dave Winkler <[email-masked]>
Subject: Re: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?

I too have done semiempirical MO calculations on molecules containing sulfur 
(sulfones and sulfoxides) and have obtained the same behaviour.  I would be very 
interested in what you discover.  I had some doubt about the size of the charges 
but felt that a highly polarizable atom like S, covalently bonded to two 
oxygens, may have quite a high charge.  Please send me any relevant information 
coming out of this discussion. 

What about a fixed geometry calculation on something small like DMSO using ab 
initio methods? 
**************************

From: "Andrey Bliznyuk" <[email-masked]>
Date:          Mon, 27 Jun 1994 17:36:15 
Subject:       Charges on S

It is not clear from your letter, which charges are you going to use.
It seems, that you are speaking about Mulliken charges. This charges
are not supposed to be used in molecular mechanics calculations, 
because
they do not reproduce electrostatic potential around your molecule.
The appropriate way is to use charges generated from electrostatic
potential calculation. Most programs can do that.
Recently, interesting method have been introduced:
  G.P. Ford, B. Wang - J. Comp. Chem., 1994, v.15, p.200-207.
Ordinary, using such methods you receive hypervalent charges
for S / P around 1.8. The problem is that hypervalent S and P
are unaccessible. There is a way around:
  C.I. Bayly, P. Cieplak, W.D. Cornell, P.A. Kollman:
  J. Phys. Chem., 1993, v.97. p.10269-10280.
but, as far as i know, it is not implemented in Ampack/Mopack.
Fortunately, for most of the calculations, it is not very important,
because the electrostatic potential around molecule is good enough.
My experience (for P) is that AM1 charges, derived from electrostatic
calculations are good.

The Mulliken charges looks ok for me, for example for H2SO4:
        MNDO            = 1.7483        - not parametrizied for 
hypervalent
        AM1             = 2.8734
        PM3             = 2.5095
        MNDO/d          = 2.3401        - d orbitals on S.

P.S. There are some confusing about Mulliken charges in semiempirical
     calculations. Here, i am using the standard (in NDO 
approximation)
     definition:
     q(atom a) = Sum(i of a) Pii, where Pii is diagonal elements of
     density matrix.
**************************

Date: Mon, 27 Jun 1994 10:27:50 +0200
From: [email-masked]
Subject: sulphur things

I just read your email to CCL on sulphur cpds. I tried CHARGE3 in XED (as I 
expect you have anyway) and found that the charge on the S was +0.2937 . I 
realise that CHARGE3 is empirical, but MOPAC is semi-empirical. with 
differences between Hamiltonians.  

...stuff deleted...

Even when using ab initio ESPs the 
situation is not clear cut as there is also a basis set dependence. I think 
you should use the charges you think give the 'best' results, as long as 
you are consistent in the use of charge models and use a 'standard' of some 
sort (not much of a problem as there are lots of standards to choose from).

I believe the correct international (IUPAC) name for sulphur is sulfur, but 
I don't think phosphorus was 'changed' for the benefit of 'global 
communications'.
**************************

Date: Mon, 27 Jun 94 10:50:26 +0100
From: "Wojciech Galazka" <[email-masked]>
Subject: Re: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?

And did you include d-orbitals to your calculations? Look for SIBIQ 
program that uses MNDO/d scheme.
**************************

Date: Mon, 27 Jun 1994 12:03:24 -0400 (EDT)
From: [email-masked]
Subject: Re: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?

I am also interested in the "correct" atomic charges one should use for
the sulfone group.

I do not have access to programs like G92, so I am interested in your
results.  Have you performed any G92 calculations on your model
molecule CH3-SO2-NH-CH3, or just semi-empirical calculations?

A few years ago I found a paper in which the charge of the S in the
sulfone group was apparently found to be about 0.9 through some sort
of spectroscopy that I am not familiar with.  I'm not positive about
this number, because the paper was written in Russian (which I do not
understand).  The number 0.9 appeared in a table in this paper, so I
may or may not be interpreting it correctly.  I can probably find this
paper in my files and provide you with the reference if you are
interested.
**************************

From: "Christian Boehme"  <[email-masked]>
Date:         Mon, 27 Jun 1994 18:41:01 MDT
Subject:      Re: CCL:Semi-empirical S-charge: 'right' or 'wrong' ?

To me your results sound reasonable. If you use a semipolar bonding 
model for this hypervalent compound (which is preferred by a lot of 
theoretical chemists instead of d-orbital participation), the charge 
should be around 2.0. I obtained the following Sulfur charges for SF6, 
using an 6-31G* basis on RHF level :
Mulliken : 2.4
Natural Population Analysis : 3.2
Bader s Atoms In Molecules : 4.5
Semipolar bonding suggests a charge around 3.0. So the higher values 
you obtained may even be the more reasonable ones. Of course you re 
right in your opinion that atom charges are only a model. I ve recently 
read a reference which compared different methods to derive such 
charges. I don t have it at hand but if you re interested, just send me a 
note. Greetings,
**************************

Date: 27 Jun 94 14:21:00 EST
From: "DR. LIOTTA" <[email-masked]>
Subject: sulfonamide (repeat message - new address found)

 I only caught the second message you sent to the CCL     
 but I am very interested in your test model for the  
 sulfonamide bioactive compound. I am trying to model
 a similar compound, but need to find the v1, v2 and v3
 torsional vibration parameters for -S(O2)-N(CH3)-C(sp3)-OH,
 -S(O2)-N(CH3)-C(sp3)-C(sp2) and -S(O2)-N(CH3)-C(sp3)-C(sp3) 
 Have these been calculated before and if so could you tell me 
 where they are published. Thank you.
 Veronica Cornel
**************************

Date: Tue, 28 Jun 1994 09:52:13 -0400
From: [email-masked] (Enrico Purisima)
Subject: CCL:Sulfonamide

Two papers that derive force-field parameters for sulfonamides are:

Nicholas et al., "A Molecular Mechanics Valence Force Field for
Sulfonamides Derived by Ab Initio Methods." J. Phys. Chem. 95:9803-9811
(1991).

Bindal et al., "Ab Initio Calculations on N-Methylmethansulfonamide
and Methyl Methanesulfonate for the Development of Force Field Parameters
and Their Use in the Conformational Analysis of Some Novel Estrogens."
JACS 112:7861-7868 (1990).
**************************

From: Paulo Henrique Guadanini <[email-masked]>
Subject: S-charges
Date: Mon, 27 Jun 1994 17:18:30 -0300 (EST)

Hi Moret, I calculated charges for your model compound (CH3-SO2-NH-CH3)
using 2 ab initio wave functions (table) . Note that S  ESP charge
for HF/6-31++G** wave function is 2.5 times smaller than  others theoretically
derived charges.  I included also charges calculated more empirically by
the Charge Equilibration method 
(A.K.Rappe and W.A.Goddard III, J.Phys.Chem. 95,3358(1991)). In this case 
the S charge have opposite sign. Due to the modest computational
costs, you may try to use methods based on the electronegativity 
equalization approach to calculate charges for the bioactive compounds.
See, for example 
J.Mullay J.Comp.Chem. 9(7), 764(1988)
J.Mullay J.Comp.Chem. 12(3), 369(1991)
W.J.Mortier, et al J.Am.Chem.Soc. 107,829(1985)
W.J.Mortier, et al J.Am.Chem.Soc. 108,4315(1986)
T.K.Ghanty and S.K.Ghosh THEOCHEM 276, 83(1992)
J.Gasteiger and M.Marsili Tetrahedron 36,3219(1980)
A.K.Rappe and W.A.Goddard III, J.Phys.Chem. 95,3358(1991)

     HF/6-31G   HF/6-31G   HF/6-31++G** HF/6-31++G**  Charge
     Mulliken    CHELPG     Mulliken     CHELPG       Equilibration
H     .175192   -.063406   .171631    -.083289        .15623
H     .052421   -.168608   .006913    -.208642        .08554
H     .540226    .371062   .501927     .392285        .26842
H     .211525    .067218   .168815     .062701        .11286
C    -.949472   -.111049  -.752617     .114410       -.07299
S    1.230307   1.166504  1.433971     .519700**     -.09075**
N    -.514572   -.065378  -.446039     .086295       -.24547
C    -.182035   -.092049  -.252464    -.026867       -.20924
H     .232512    .007172   .174369    -.029782        .15315
H     .243595    .158310   .187150     .151572        .13459
H     .255879    .104173   .210553     .095389        .17736
O    -.677410   -.694042  -.767149    -.552283       -.21774
O    -.618167   -.679908  -.637061    -.521488       -.25194
**************************

From: "Chris L. Waller" <[email-masked]>
Date: Fri, 1 Jul 1994 10:17:12 -0400
Subject: Re: CCL:Semi-empirical S-charges II

About sulfonamides: I ran a DFT calculation on your test molecule using a DNP
(double numerical with polarization functions) basis set and obtained the
following charges:

 Effective atomic charges from Mulliken populations:
  O #  1 -0.457
  S #  2  0.929
  O #  3 -0.455
  C #  4 -1.092
  N #  5 -0.652
  C #  6 -0.906
  H #  7  0.362
  H #  8  0.388
  H #  9  0.395
  H # 10  0.460
  H # 11  0.354
  H # 12  0.337
  H # 13  0.336

This was a single point energy calculation on the PM3 optimized structure.
**************************

End of the replies.
-------------------------------------------------------------------------
E.E. Moret	(@more@)			    [email-masked]
Computational Medicinal Chemistry/Department of Pharmaceutical Chemistry
Faculty of Pharmacy/Utrecht University/the Netherlands
Telephone	(31-30)536979/536958        Facsimile      (31-30)516674
-------------------------------------------------------------------------