Subject: charges again

From: Nicholas Tomkinson <[email-masked]>
Date: Tue, 21 Feb 1995 09:57:00 +0000 (GMT)

Dear all,
  
  Once more with feeling. Thanks to Konrad for helping reformat this.
  Thank you to all who posted responses. Based upon the response and
  a second trawl through the archive I shall be using MNDO for my comfa
  charges in future. I shall probably still use AM1 for optimisation. 
  (The quality of charges from each method is assessed in a paper by Carlos 
  Aleman published in J.Comp.Chem. vol 14 799-808 (1993).)
  I tend to agree with Konrad Koehler who suggests that random errors 
  in charge schemes will just add noise to a CoMFA analysis. This will be less
  than the error introduced by being inconsistent I should think.
  
  ################################################################################
  I have two statements and a question for you.
  
  1) My experience of fitting charges using CHELPG to ab initio results
  indicates that the charges you get vary somewhat due to conformation (10-20%).
  As I'm using MD I just use an "average charge". 
  
  2) As I'm sure many others will tell you Mulliken charges bear little
  resemblance to the charges produced by any of the ESP fit methods.  This can
  have a pretty significant effect on your calculation.  I looked at MNDO, AM1,
  PM3 and ab initio (up to 6-31G*).  Basicly, MNDO Mulliken analyses are closest
  to the ESP fits of the ab initio calcs.  AM1 produces larger charges and PM3
  larger charges still. PM3 charges were about 60% greater than MNDO ones in
  some cases.  It may be slow and painful, but the only way to quality results
  is an ESP fit (to MNDO results should be fine).  You might be able to save
  yourself some time by reducing the mesh of points where you are doing the
  fitting to cover those parts of the molecule that are of real interest or
  where there is significant charge seperation. 
  
  3) Where did you get your ESP fitter for MNDO or can I get a copy of it.  I
  only have one thats part fo an ab initio package and I would love to have one
  that I could use with my semi-empirical package. 
  
  P.S.    In defense of MNDO.  I started out using the other two methods (AM1
  and PM3) and found that they didn't do nearly as good a job at evaluating the
  energy of conformers.  There are several articles in J. Comp. Chem. which
  compare the methods and indicate that MNDO did the best job.  PM3 seriously
  overestimates the attraction between methyl groups.  AM1 does better but is
  still too attractive. MNDO is a little too repulsive but is still the closest
  fit to ab initio results. 
  
  Dr. Ross Underhill
  Royal Military College of Canada
  Kingston, Ontario
  (613) 541-6000 X6175
  #############################################################
  ###################
  Nicholas
  
  I am often concerned with validity of partial atomic charges.  The method I've
  settled on for small molecules involves full geometry optimization using AM1
  (the later versions handle sulfur), then resubmitting for an ESP-MNDO
  calculation with no geometry optimization (there's a hiccup with this in that
  my version of sybyl generates a .dat file specifying full geometry
  optimization regardless of what one wants, so I submit the MNDO ESP file on
  "hold for later" without specifying "user other MOPAC" [this generates the
  proper .dat file], then outside sybyl do a "RunMopac etc").  My concern about
  using MNDO for the geometry optimization as well is related to inaccuracies in
  the charge calculations which I thought could arise in systems with partial
  double bonds which MNDO might not recognize too well, giving "twisted" groups
  which should be planar (and undergoing resonance). The slowness of ESP is a
  problem but I believe recently is has been sped up considerably.  I would put
  more trust in charges derived from this than from PM3 Mulliken, although I too
  have also read that consistent use of a certain method, rather than the method
  itself, may be more important for CoMFA/Docking etc. CoMFA is potentially a
  great method, although I would like to see the ability to incorporate
  hydrophobic fields (which can be done by interfacing to HINT, by G. Kellogg)
  and flexible molecules should be used with caution.  People have suggested
  various dielectric constants for emulating a protein interior (which is I
  suppose what you are after), varying from 4 to something in the 30s, as an
  alternative to a distance-dependant dielectric, but I am unaware of one being
  a "clear winner". As a chemist with little time recently for modelling, I
  would like to validate the above, which are essentially "hunches"; please can
  I see your answers if you don't post them to the net. 
  +----------------------------------------------------------------------Dr 
  Jonathan Ball
  CSIRO,  Division of Animal Health
  Private Bag 1, Parkville, Victoria 3052
  Australia
  Internet email: [email-masked]
  Tel: +61 3 342-9782   Fax: +61 3 347-4042
  ______________________________________________________________________
  ################################################################################
  Dear Dr. Tomkinson,
    I read with interest your comments about semiempirical charges for CoMFA
  work. I have a few comments that may be helpful in the context of your
  questions: 
  -  PM3 is known to be unreliable for charges.  The reasons for this are
  relatively well-known, but I would certainly NOT depend on these charges for
  analyses such as you are carrying out.  While certainly    not perfect, I
  think that AM1 is usually considered to be more reliable than PM3 for
  quantities related to analysis of the molecule's wavefunction.  AM1 can be
  found in many places, especially the various versions of AMPAC amd MOPAC now
  available.  The AM1 reference is: Dewar, M. J. S.; Zoebisch, E. G.; Healy, E.
  
  F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902. 
  -  I would NEVER recommend using Mulliken-derived charges with a minimal basis
  set semiempirical method like AM1 or PM3.  The basis set dependency of
  Mulliken makes the application of this method essentailly invalid.  I hope
  that when you WROTE "Mulliken" you MEANT "Coulson".  This is the technique
  that is used by default in both AMPAC and MOPAC and these charges are those
  that are reported in the OUT and ARC files resulting from these programs. 
  References to the Coulson approach are: 1) Armstrong, D. R.; Perkins    P. G.;
  Stewart, J. J. P. J. Chem. Soc., Dalton 1973, 838; 2) Pople, J. A.; Beveridge,
  D. L. Approximate Molecular Orbital Theory; McGraw-Hill: New York, 1970; pp
  67. 
  -  Both MNDO and AM1 have sulfur parameters in modern implementations of the
  methods. 
  -  ESP is a good charge method and may run much faster in some programs than
  others.  You should look around. 
   Cheers, Andy Holder
  =3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-
  =3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-
  ANDREW HOLDER
  Assistant Professor of Computational/Organic Chemistry
  Department of Chemistry
  Internet Addr: [email-masked]
  Univ. of Missouri - Kansas City
  Phone Number:  (816) 235-2293 Spencer Chemistry, Room 315
  FAX Number:    (816) 235-5502
  Kansas City, Missouri 64110
  =3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-
  =3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-=3D-
  
  ################################################################################
  
  Hi Nicholas,
  Partial charges can be calculated from wave functions (semiemp or ab initio)
  by the Mulliken or ESP, among other methods. The ESP method is better because
  is less basis set dependent and reproduces dipole moments much better than
  Mulliken charges. So I would recommend the use of ESP. I'm using AM1 and ab
  initio 321G* results and they show the same  trends in dipoles calculated from
  ESP charges (it doesn't happen with Mulliken). The trends are for many
  conformations of 20 - 50 atoms molecules. Now, if you need something faster
  that also reproduces dipoles you can use Charge Equilibration method from
  Rappe & Goddard, J.Phys.Chem., 95,3358-3363,1991. It's realy fast and you
  don't even need a wave func. 
  Edgardo Garcia Univ. of Colorado BOULDER CO  USA
  
  ################################################################################
  Subject: Re: CCL:charges schemes with CoMFA
  You might want to read the material on charge fitting under
  http://www.amber.ucsf.edu/amber/amber.html - also there are pages on charges
  and semiempirical charges under the 'material from the net' heading. 
  Bill Ross
  ################################################################################
  
  Subject: Re: CCL:charges schemes with CoMFA
  See J. Med. Chem. 1993, 36, 2390.
  
  I that paper, I performed a CoMFA on ACE inhibitors using PM3 charges. The
  original manuscript in that series used the same alignment rule but
  Gast_Marsili charges. I did find that PM3 charges worked somewhat better. In
  the HIV model that we published in JMC last year, we used AM1 charges. Not
  included in that paper is the model based on Gast_Huck charges which was
  comparable. ESP charges seem to be vogue right now. In essence, I don't think
  it really makes all that much difference as long as you are comfortable with
  the charge set (i.e. it gives reasonable looking charge distributions) and you
  are consistent in your treatment. 
  CW
  ################################################################################
  *Chris L. Waller, Ph.D.                          PHONE 919-541-7976*
  *Research Chemist                                FAX   919-541-5394*
  [email-masked]                                          *
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  ################################################################################
  Subject: Re: CCL:charges schemes with CoMFA
  
  You missed our papers!!  Although we didn't compare AM1 with PM3 in this 
  application, we see very strange charges with PM3 on nitrogens.  AM1 gives good 
  CoMFA models that fit & cross-validate pKa's. Pertinent references:
  
  K. H. Kim, Y. C.  Martin, Chapter in "QSAR: Rational Appraoches on the Design 
  of Bioactive Compounds", C. Silipo and A. Vittoria, Eds., Elsevier, 
  Amsterdam.", 1991 "Evaluation of Electrostatic and Steric Descriptors for 
  3D-QSAR: The H+ and CH3 Probes Using Comparative Molecular Field Analysis 
  (CoMFA) and the Modified Partial Least Squares Method" pp 151-154. 
  
  Ki. H. Kim and Yvonne C. Martin, J. Org. Chem., 56, 2723-2729, 1991, =D2Direct
  Prediction of Linear Free Energy Substituent Effects from 3D Structures Using
  Comparative Molecular Field Analysis. 1. Electronic Effects of Substituted
  Benzoic Acids=D3. 
  
  K. H. Kim and Y. C. Martin, J. Med. Chem., 34, 2056-2060, 1991 =D2Direct
  Prediction of Dissociation Constants (pKa=D5s) of Clonidine-like Imidazolines,
  2-Substituted Imidazoles, and 1-Methyl-2-substituted-imidazoles from 3D
  Structures Using a Comparative Molecular Field Analysis )CoMFA) Approach=D3. 
  
  In unpublished work, we also found that AM1 is just fine for phenols and
  anilines, provided that one uses the unprotonated form for the structure
  optimization. 
  
  Yvonne Martin, Senior Project Leader
  Computer Assisted Molecular Design Project
  D-47E, AP10 2fl
  Abbott Laboratories
  100 Abbott Park Road
  Abbott Park, IL 60064-3500
  Phone: 708 937-5362 FAX: 708 937-2625>
  PS. The JOC article has the most comparisons.
  ################################################################################
  
  Nick:
  
      My preference for CoMFA are ab initio 6-31G* ESP fitted charges.[1,2]  If
  you only optimize bond lengths and valence angles and hold torsions fixed,
  these calculations are not as time consuming as you might think. 
  
      If you wish to use semiempirical methods, check out the PMEP option [3,4]
  in the most recent version of MOPAC93.  It is at least 2 orders of magnitude
  faster than the Besler et al. method and more accurate.  The method is
  currently parameterized for C,H,N,O,F, and Cl.  The author ([email-masked]) is
  currently working on parameters for S and P. 
  
      I suspect that the charges are more important than what dielectric
  constant you use.  For a more radical approach, you might check out a recent
  paper by Klebe et al.[5].> 
  
      I hope you find these references useful.
  
      Ciao,
  
  Konrad
   ------------------------------------------------------------------ 
  | Konrad Koehler              |  Computational Chemistry Group     |
  | internet:  [email-masked]  |  Department of Medicinal Chemistry |
  |                             |  IRBM                              |
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  (1) Allen, M. S.; La Loggia, A. J.; Dorn, L. J.; Martin, M. J.; Costantino,
      G.; Hagen, T. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. Predictive
      binding of b-carboline inverse agonists and antagonists via the
      CoMFA/GOLPE approach. J. Med. Chem.   1992, 35, 4001-4010.
  (2) Wong, G.; Koehler, K. F.; Skolnick, P.; Gu, Z.-Q.; Ananthan, S.;
      Schonholzer, P.; Hunkeler, W.; Zhang, W.; Cook, J. M. Synthetic and
      Computer Assisted Analysis of the Structural Requirements for Selective,
      High Affinity Ligand Binding to 'Diazepam-Insensitive' Benzodiazepine
      Receptors. J. Med. Chem.  1993, 36, 1820-30.
  (3) Ford, G. P.; Wang, B. A new approach to the rapid semiempirical calculation
      of molecular electrostatic potential based on the AM1 wave function:
      Comparison with ab initio HF/6-31G* results.  J. Comput. Chem.   1993, 14,
      1101-1111.
  (4) Wang, B.; Ford, G. P. Atomic charges derived from a fast and accurate
      method for electrostatic potentials based on modified AM1 calculations.
      J. Comput. Chem.   1994, 15, 200-207.
  (5) Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a
      comparqative analysis (CoMSIA) of drug molecules to correlate and predict
      their biological activity.  J. Med. Chem.   1994, 37, 4130-4146.
  ################################################################################
   Nicholas:
  There have been publications confirming that CoMFA models are charge-scheme
  insensitive; see Kubinyi, "3D QSAR in Drug Design", ESCOM, Leiden, 1993, for
  review articles summarizing the CoMFA technique.  In my hands,
  Gasteiger-Huckel assignment of charges appears to give CoMFA models that are
  much the same as those using charges from semiempirical calculations. 
  Phil Cruickshank
  
           *************************************************************
           *    Philip A. Cruickshank                                  *
           *    FMC Corporation, Agricultural Chemical Group           *
           *    Chemical Sciences Team                                 *
           *    P. O. Box 8, Princeton, NJ 08543                       *
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  ################################################################################
   Hi Nick, 
  Hope things are fine at Loughborough. If you want a semi-emp method for charge
  calculations then the SAM1 method has had some good publicity lately, it
  handles phosphrous and sulphur better than AM1. Try talking to Andy Holder
  ([email-masked]), you may want to get hold of AMPAC 5.0 for this, which
  if your quick you can get a 30 day trial copy... 
  TTFN Andy -- 
  ################################################################################
  Structural and Computation Chemistry [email-masked] - JANET. 
  Department of Chemistry___________________________phone_______+44-1483-259591. 
  University of Surrey______________________________fax_________+44-1483-300803. 
  Guildford,________________________________________ftp___________131.227.110.69 
  Surrey, GU2 5XH, UK_________________WWW  http://www.chem.surrey.ac.uk/~chp1aa/ 
  ################################################################################
   ################################################################################
   Subject: Re:  charges schemes with CoMFA
  
  I will not discuss the impact of choosing partial charges in conformational
  analysis (CA), for two reasons: their magnitude (and "correctness") will
  influence the choice of your local minima [to the extent that empirical
  charges may give a different energy map than quantum-mechanical ones], and the
  choice of the dielectric D will definitely contribute to that [smaller D will
  result in higher probability of intra-molecular H-bonds]. MNDO ESP
  calculations may be slow in MOPAC, but they correlate well with 631G* ESP
  charges - 0.94-0.96 R^2 for charge to charge correlation - better than STO-3G
  ESP for the same molecules [these with G92]. PM3 has been previously reported
  to go wrong with Nitrogens - it was previously posted on CCL - so browse in
  the 93-94 archive and look for messages from Drs JJP Stewart, A Holder, E
  Zoebisch [and others...]. 
  
  In CoMFA, the choice of charges does not matter as long as you are consistent
  throughout the series: "If you can't be right, be consistent" (David
  Patterson). In my experience, MNDO vs MNDO ESP charges have no significant
  impact on the sets I studied. Of course, there might be some tricky ones out
  there 8=3D) but for systems where no fancy electronic distribution occurs,
  MNDO or AM1 can do the works. Chris Waller has noted that PM3 gives better
  correlations than Gasteiger- Huckel, but I would point out that both models
  were correlating well in CoMFA. A paper I reviewed (I believe it is out in
  JMC) reported on the side that comparing AM1 vs Gasteiger-Marsili, they found
  no difference. In sum, as long as your CA results are ok, your CoMFA model is
  unlikely to yield significant differences by using different partial charges.
  As for the dielectric in CoMFA - I recently started using constant D instead
  of distance dependent one - again, it is unlikely to have a tremendous impact
  on the robustness/predictive/explanatory qualities of your model. 
  --Tudor
  **************************************************************
  *  Tudor I. Oprea, MD PhDTel: (505) 667 2682                 *
  *  Postdoctoral Research AssociateFax: (505) 665 3493        *
  *  Theoretical Biology and Biophysics (T-10)Email:           *
  *  Los Alamos National [email-masked]          *
  *  Mail Stop K710, Los Alamos NM 87545                       *
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  #################################################################################
  #
  
     On 10-FEB-1995, Tudor Oprea wrote in response to Nick Tomkinson's post:
  
  > MNDO ESP calculations may be slow in MOPAC, but they correlate well with
  > 631G* ESP charges - 0.94-0.96 R^2 for charge to charge correlation -
  > better than STO-3G ESP for the same molecules [these with G92].
  
     The latest version of MOPAC93 includes a new option, PMEP[1,2] which is at
  least two orders of magnitude faster and more accurate (at reproducing 6-31G*
  ESPFIT charges) than the old MOPAC ESP charges.
  
  [1] Ford, G. P.; Wang, B. A new approach to the rapid semiempirical calculation
      of molecular electrostatic potential based on the AM1 wave function:
      Comparison with ab initio HF/6-31G* results.  J. Comput. Chem.   1993, 14,
      1101-1111.
  [2] Wang, B.; Ford, G. P. Atomic charges derived from a fast and accurate
      method for electrostatic potentials based on modified AM1 calculations.  J.
      Comput. Chem.   1994, 15, 200-207.
  
  > In CoMFA, the choice of charges does not matter as long as you are consistent
  > throughout the series: "If you can't be right, be consistent" (David Patterson
  ).
  > In my experience, MNDO vs MNDO ESP charges have no significant impact on
  > the sets I studied. Of course, there might be some tricky ones out there 8=)
  > but for systems where no fancy electronic distribution occurs, MNDO or AM1
  > can do the works. ... [rest of message deleted]
  
     The source of charges may not matter for systems like steroids or peptides,
  where most commonly used methods (including Gasteiger-Marsili) give reasonable
  charges.  But in my experience, the source of charges does make a _big_
  difference for systems such as aromatic heterocycles.  We did a comparison of
  ESPFIT 6-31G* [3] vs. MNDO//PRDDO/ESPFIT [3] vs. Gasteiger-Marsili
  [unpublished].  The cross validated R2's were 0.71 vs. 0.65 vs. ~0.40
  respectively.
  
  [3] Allen, M. S.; La Loggia, A. J.; Dorn, L. J.; Martin, M. J.; Costantino,
      G.; Hagen, T. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. Predictive
      binding of b-carboline inverse agonists and antagonists via the
      CoMFA/GOLPE approach. J. Med. Chem.   1992, 35, 4001-4010.
  
      The use of consistent charges will of course cancel systematic errors in
  the charges.  However, if the errors are random and if the electrostatics
  (relative to sterics, hydrophobicity, etc.) are an important part of the
  correlation, then bad charges will produce bad correlations.
  
      Ciao,
  
   ------------------------------------------------------------------
  | Konrad Koehler              |  Computational Chemistry Group     |
  | internet:  [email-masked]  |  Department of Medicinal Chemistry |
  |                             |  IRBM                              |
  | telephone: +39-6-910-93606  |  Via Pontina Km. 30,600            |
  | fax:       +39-6-910-93225  |  00040 Pomezia (Roma)              |
  |                             |  Italy                             |
   ------------------------------------------------------------------
  
  #################################################################################
  #
   Subject: Re: CoMFA charges>
  Hi -
  In regards to your question on charges.  We have developed a method for
  obtaining partial charges that we call Charge Model 1 (CM1).  The method is an
  empirical mapping of the Mulliken charges obtained by either AM1 or PM3.  Of
  course, everyone has their favorite method for computing partial charges and
  there is no way to compare directly to experimental measurements.  When
  developing CM1, we chose our method so that the dipole moment calculated from
  our partial charges reproduced the experimental dipole moment for that
  molecule as closely as possible. Calculating CM1 charges takes essentially no
  more time than the PM3 calculations that you are already running but they are
  much more accurate.  We have incorporated CM1 into our program AMSOL which is
  available from QCPE.  The paper describing our method is currently in press in
  the Journal of Computer- Aided Molecular Design (I unfortunately don't have a
  release date to give you). We find that, in general, when compared to
  experiment, dipole moments calculated with CM1 yield about the same accuracy
  as dipole moments calculated from HF/6- 31G* CHELPG charges, or even the
  MP2/6-31G* density derived dipole moments.  CM1 has been developed for H, C,
  N, O, F, Si, S, Cl, Br, and I.  I'd be happy to send you more information if
  you'd like. 
  David J. Giesen [email-masked]
  #############################################################