|
|
| From: |
marty "at@at" ionchannel.med.harvard.edu (Marty Gallagher) |
| Date: |
Fri, 1 Oct 93 17:26:48 -0700 |
| Subject: |
torsion of conjugated systems -- summary |
Hello,
I am posting a compilation of all the responses I got concerning
the question I had posed:
|> Does anyone know a forcefield which includes a term for
|> torsional energy in a conjugated system? Specifically, I am
|> interested in rotating the carbonyl in acetophenone out of plane
|> with the phenyl ring. MOPAC geometry optimization places the
|> carbonyl in the plane of the ring. Without running a dozen
|> MOPAC runs, can I get an estimate of what the energy would be
|> out of the plane?
To give some background on the problem:
I had originally used one molecular mechanics program (which I'll leave nameless
because its
failure could easily have been due to my own naivete rather than lack
of
parameterization) which said the lowest confomer was 90 degrees! Since last
week when I've tried it again using a different MM package, (biosym's discover),
the lowest confomer is at 0 degrees which is 10 kcal lower than the confomer
at 90 degrees. The phi potential accounted for almost 100% of the energy
difference
Hopefully, this will result will be similar to the MOPAC run which I am
performing
now. The reason I hope that I can perform these calculations via MM rather than
QM is because I am really not interested in acetophenone, but in compounds that
that have that conjugated system plus 5-8 other interesting dihedral angles.
I realized that searching enough of conformational space with these many
torsional angles is prohibitive enough without throwing in any QM calculations.
Thank you, everyone who wrote! I learned quite a bit.
===================================================================
| |
| Martin J. Gallagher |
| Dept of Neurobiology |
| Harvard Medical School |
| 220 Longwood Ave |
| Boston, MA 02115 |
| (617) 432-1729 |
| |
| marty(-(at)-)ionchannel.med.harvard.edu |
| |
===================================================================
responses:
================================================================================
Unfortunately, I can not really help you here. An arguement in favor
of doing the dozens of MOPAC runs: there will be significant electronic
state shifts as you distort the conjugated system likely leading to
significant changes in charge distribution. No empirical force field
is going to get these right. Electrostatics and hydrogen bonding are
critical deteriminants of specificity in many active sites, and Ray
Salemme argues convincingly that most really tight ligand/protein
interactions involve some sort of "special" chemistry such as
cooperative hydrogen bonding. With some semiempirical data, you
at least have a shot at getting on handle on these.
David States, Director, M.D., Ph.D. '83 (Harvard Med/Biophysics)
Institute for Biomedical Computing
Washington University in St. Louis
Pieter Stouten writes,
Conjugated pi-systems constitute one of the larger issues in the
development of force fields that describe macromolecule-drug interactions
adequately.
Anyone interested in this may like to contact M.J.Bearpark, M Olivucci or
M.A.Robb who gave a lecture on "Large active space valence bond methods:
application to conjugated polycyclic hydrocarbons"
This theory takes an MM sigma framework then uses ab-initio parametering on
top to modify the force constants, I could not follow most of the technical
side of how this was done but the results looking promising.
Email address:
max %-% at %-% gandalf.ciam.unibo.it (Olivucci)
udca700 "at@at" oak.cc.kcl.ac.uk (M.A. Robb)
no email for Bearpark.
Andy.
Martin,
The problem you pose, as I understand it is - How
do you determine the energy of a conjugated acetophenone
with the acetyl group tilted out-of-plane to various degrees?
With that in mind, what you need to use it the "dihedral
angle driver" that is present in either MOPAC (MNDO or AM1),
or in a variety of molecular mechanics programs such as MM2,
etc. The principle involved is simply rotating the selected
dihedral angle through the desired arc, using the desired
increment, and doing without minimization, or geometry
optimization) an energy calculation at each point. I have
in the past used SYBYL SEARCH, and MacroModel to do this.
I believe MNDO also has a similar routine, but I have not
used it.
Additionally, SYBYL or AMBER will do the rotation, hold
the rotatable angle fixed, and minimize the rest of the
molecule, which is also a very good idea. Molecular mechanics
should be as good, or better than, a semi-empirical method for
the shape of a molecule for which it is well parameterized.
It should also give good relative energies between different
conformations of the same molecule, and between similar molecules.
Molecular mechanics also has the virtue of being faster.
If I can be of any further help let me know.
I love your library on Longwood. I was a chemistry
graduate student at MIT (about 20 years ago) and had the
opportunity to use the library there, since my thesis involved
mimicry of some features of biological catalysis,and some of the
literature in which I was interested was not available at the
Institute.
Good luck, and best wishes,
Dick
************************************
* Richard W. Harper, Ph.D. *
* Eli Lilly & Company *
* Lilly Research Laboratories *
* Lilly Corporate Center *
* Indianapolis, IN 46285-0444 *
************************************
* (317) 276-5990 Voice *
* (317) 276-5187 Fax *
* EMail HARPER_RICHARD_W -8 at 8- lilly.com *
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From: HARPER RICHARD W (MCVAX0::WALTZ)
To: FOREIGN TRANSPORT ADDRESSEE (MCDEV1::IN%"marty (- at -)
ionchannel.med.harvard.edu")
cc: HARPER RICHARD W (MCVAX0::WALTZ)
You could do a literature search (CAS on-line) to find out if it's
been done. But if it hasn't, what's wrong with a dozen MOPAC
runs? You could do it as a reaction coordinate with 1 input file.
If you left it on a VAX Friday night, it would probably be done
Monday AM...
Irene Newhouse
Marty,
My advice to you is to perform your calculations using the HF/6-31G*
theoretical model within a program like Gaussian9x. The energies
that you are interested in examining are going to be quite sensitive
to the methods used in determining them, so it pays to use a certain
minimum level of theory which has been proven to work in cases like this.
I realize that you may not want to commit the time and resources to
an ab initio study, but you will get much better results if you do.
Curt Breneman
Asst. Professor of Chemistry
Rensselaer Polytechnic Institute
Troy, NY 12180
breneman-: at :-quant.chem.rpi.edu (and others)
In some recent postings to the Computational Chemistry List the issue of
force fields for conjugated pi-systems was brought up. Marty Gallagher
ionchannel.med.harvard.edu> wrote:
> Does anyone know a forcefield which includes a term for
> torsional energy in a conjugated system?
>
Conjugated pi-systems constitute one of the larger issues in the
development of force fields that describe macromolecule-drug interactions
adequately. Efforts generally seem aimed at sort of ad hoc development of
parameters for a small number of closely related compounds. Often times
these will not be transferable and consistent with parameters that have
been developed in the same vein for other compounds containing the same
functional groups. We are in desparate need of a concerted effort towards a
consistent treatment of conjugated pi-systems. I sincerely hope this will
be a (the ?) main focus of the Biosym Potential Energy Forcefield
Consortium over the next years. I also hope that more institutions will
join the consortium so that the development of the force field can be
given some more momentum.
Pieter Stouten, Senior Research Scientist ||
Computer Aided Drug Design Group ||
The Du Pont Merck Pharmaceutical Company || Adventures get spoiled
P.O. Box 80353, Wilmington, DE 19880-0353 || by being reduced to data
Phone: +1 (302) 695 3515 || --
Fax: +1 (302) 695 2813 || Poul Anderson
ARA/Fax: +1 (302) 695 4324 ||
E-mail: stoutepf %! at !% chemsci1.es.dupont.com ||
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On Wed, 29 Sep 1993, Marty Gallagher wrote:
> Does anyone know a forcefield which includes a term for
> torsional energy in a conjugated system? ...
Hi!
You may find that most molecular mechanics programs include such terms.
Programs that you may consider:
Peter Kollman's Amber
Allinger's MM2 series (look at MM3 I think they have addressed
a problem similar to yours)
CharmM (Chemistry Dept. at Harvard)
Gromos
Also, check out papers by Beveridge published possibly in JACS in the
'60's - '70's. He did a torsional analysis on acetylcholine and
you may get ideas on how to proceed with your work.
gus mercier
mercie (+ at +) cumc.cornell.edu
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Martin;
Just set the dihedral angle of interest to whatever value
you wish, such as 90 degrees. Also, change the optimization flag
from one to zero for the dihedral you just changed. MOPAC will
optimize the geometry to at least a stationary point (not
necessarily a minimum) without rotating the dihedral angle.
If you are using the QCPE Draw program to create the
input data set this will be easy. Other packages will also
provide ways to "fix" an geometry spec. so that it is not
adjusted during optimization. You'll have to check the manual
for the program you are using. Alternatively you could go to the
operating system, use the editor and make the changes you need
(This assumes you can identify the atoms in the data file.)
Good Luck,
Fred
Just for fun I constructed acetophenone and ran a dihedral driver
0 to 90 degrees using the molecular mechanics program MM2(91).
I used my own molecular modeling system, MacMimic, that runs on
Macintosh II and Quadra computers, and I had the results within
three minutes.
Here is the output file from the driver. The energies are in kcal/mol.
I would expect the MM2 energies should be of very high quality (equal
to or better than MOPAC) in this case.
acetophenone
ANGLE1= 2- 3- 12- 14
0.0 0.3684
5.0 0.3751
10.0 0.4042
15.0 0.4587
20.0 0.5440
25.0 0.6647
30.0 0.8276
35.0 1.0336
40.0 1.2807
45.0 1.5633
50.0 1.8680
55.0 2.1868
60.0 2.5022
65.0 2.7946
70.0 3.0460
75.0 3.2397
80.0 3.3588
85.0 3.3918
90.0 3.3326
TOTAL ELAPSED TIME IS 123.18 SEC.
-Anders
--
Anders Sundin e-mail: Anders.Sundin[ AT ]orgk2.lth.se
Organic Chemistry 2 ok2aps-: at :-selund.bitnet
Lund University, P.O. Box 124 voice: +46 46 104130
S-22100 Lund, Sweden fax: +46 46 108209
You could look at the torsional potential in MMP2. Better yet, do the
calculations at different torsional & compare the energies.
Yvonne Martin, Senior Project Leader
"at@at" "at@at" "at@at" "at@at" "at@at" "at@at" "at@at" "at@at"
"at@at" "at@at" Computer Assisted Molecular Design Project
[ AT ] D-47E, AP9A-LL
"at@at" "at@at" "at@at" "at@at" "at@at" "at@at" "at@at" "at@at"
Abbott Laboratories
(- at -) (- at -) One Abbott Park Road
^at^ ^at^ Abbott Park, IL 60064
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#*at*# Phone: 708 937-5362 FAX: 708 937-2625
Internet: MARTINY-: at :-ABBOTT.COM
The way e.g. MMP2 handles this is to do 'pi-calculations' prior to
the molecular mechanics energy minimization. From the 'pi-calcs'
one get the bond order of the pi bonds. The bond orders are
used to scale the bond force constants and the torsional barriers
for the given pi bonds. Depending on the amount of rotation from
'normal', the bond order and hence the parameters are changed.
I guess others have used this or similar approach.
You may take a look at Burkert & Allinger: Molecular mechanics,
ACS monograph 177 (1982), p. 52 and on...
Disclaimer: I haven't used MMP2 for several years ...
-oed.
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Greetings,
I'm assuming you're talking about molecular mechanics, and not ab initio
or sem-empirical level calculations. Either of the latter would
automatically consider conjugation, and although ab initio calculations
are considered "better", they require a lot more computing power and
without a supercomputer are unsuitable for even moderate sized molecule.
Semi empirical calcs, however, can be carried out on a 486, mini, micro or
non-parallel computer for even fairly large molecules. Programs of this
type include MOPAC, AMPAC (MNDO, MNDO/3, AM1) and are available both
commercially and from QPCE (Quantum Chemistry Program Exchange at Indiana
University).
As for molecular mechanics, some of the programs have built in conjugation
terms. The one organic chemists use most is MMX.
Hope this helps
Kimberley Cousins
Cal State Univ San Bernardino
kcousins -8 at 8- wiley.csusb.edu
Force fields that include explcit conjugation effects in determining
K(stretch), L0, and V2 have been extremely valuable here at Kodak for determining
dihedral angles of extensively conjugated systems, namely MMX. This is the
forcefield found in in PCMODEL from Serena Software, and available also
in MODEL, from Kosta Steliou, now in Boston, I believe. MMX "nails" the
dihedrals of biphenyl, o-Me biphenyl, and cisoid o,o'-dime biphenyl to
within 1-2 degrees of experiment (42,58, and 72 degrees, respectively.)
within 1-2 degrees of experiment (42,58, and 72 degrees, respectively.)
It will show some effect on the torsion angle of biphenyl when substituted
4-no2,4'-nh2. It is easy to "tune the forcefiled if desired...it is editable
in a flat file.
Hope this is useful, inspite of missspelings.
John McKelvey
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Marty,
Though I don't have an in depth familiarity with MOPAC, I am fairly
well versed in QM/MM and modelling techniques. So I would assume that
the following is applicable to MOPAC. When you set up your z-matrix defining
the torsion for your carbonyl, it is possible to scan the potential energy
surface for the torsional space that you have defined for the carbonyl.
In gaussian92 the keyword is "scan". I would assume MOPAC has something
similar. You should be able (with that keyword) to define a variable - in
this case your torsion, define the increment value you would like (e.g. say
you wanted the dihedral to vary by 30 degrees each step) then add the number
of steps you would like (obviously, you can use symmetry to cut down on the
number of runs to generate a PE profile). Also as semi-empirical methods
are rather quick on most computers, you should get a very quick answer
to your problem. Hope this helps!
**********************************************
* *
* Mark A. Zottola *
* markz-0at0-chem.duke.edu *
* Department of Chemistry *
* Duke University *
* *
* 'The fault, dear Brutus, lies not with *
* ourselves, rather within our CPU's...' *
* (with due apologies to W.S.) *
* *
**********************************************
Generate one starting structure with the carbonyl out of the plane of
the ring, convert that file to a MOPAC file format, and perform the
calculation with 1SCF in the first line. This will not optimize the
geometry, but will calculate a single point energy for the input
structure. If you don't have a way to generate starting structures of
choice, let me know.
Abby Parrill
abby %! at !% mercury.aichem.arizona.edu
The University of Arizona-chemistry
I believe the MM2(or MM3) forcefield would handle this situation quite well.
It includes a dihedral driver routine which is automated. This will help you
locate the transition state of the rotation, whose energy will give you the
barrier. This may have been done for acetophenone, so I would suggest a quick
literature search would save you some time.
You probably realize this, but from the wording of the question I thought I'd
clarify. MOPAC is a semi-empirical molecular orbital method, that is
parameterized,
but not in the sense of a forcefield, ie. bond, angle, and torsion terms. If
you are using MOPAC for a torsion analysis, you can step through the angles
by placing a -1 in the column following the dihedral angle of interest, and then
put all the steps on a line at the end of the file.
If you really want just a quick estimate, just manually set the dihedral to
be out of the ring and do a single point energy calculation. Just be aware
that this geometry may not be a minima.
--
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On the assumption that it is cpu time you wish to save rather than the number
of runs, you might try PCMODEL, which has a dynamically determined conjugated
force field...built off Allingers MP1 method. We use it extensively for dyes
here
at KODAK and the MMX forcefield in PCMODEL saves us tons of time, and it runs
on pc's, mac,you-namit workstations. Available from Kevin Gilbert
812-855 1302 or Joe Gajewski 885-1192.
John McKelvet
Dear Mr. Gallagher:
Reliable net atomic charges can be found by fitting the molecular
electric potential obtained by ab initio quantum mechanical methods.
Program PDM93 also allows atomic dipoles/quadrupoles, bond dipoles, and
addition of lone pair electron sites if necessary in order to fit the
electric potential. A particularly useful feature of the program is the
transparent way in which dependency conditions are specified. I append
information about this program.
-Don Williams
Program PDM93, Potential Derived Multipoles
The following is a brief description of this program.
Molecules interact with each other via their electric potential.
PDM93 finds optimized net atomic charges and other site multipole
representations of the molecular electric potential based on a variety
of models. The program is easy to use, flexible and powerful. Results
are obtained in a single iteration and a complete error treatment is
made which includes estimated standard deviation and correlation of
variables. The program is written in Fortran 77 and runs on Unix,
Vax, and other computers with F77 capability.
Program PDM93 has a unique combination of features:
o general sites, not necessarily at atomic locations
o each site may have any combination of monopole, dipole, or quadrupole
o bond dipole model is supported
o restricted (along the bond direction) bond dipole model is supported
o provision for site dipole vectors in sp2 or sp3 directions
o selected fixed atomic charges
o selected groups of atoms with fixed charge
o atomic charge equalities or symmetry relations
o rotational invariance of site charges
o provision for optional foreshortening of X-H bonds
o comparison with Mulliken charges and Mulliken electric potential
o direct input from Gaussian-92
o generalized input from other quantum mechanics programs
o automatic generation of electric potential grid points
o provision for custom generation of grid points
o on-line program manual
o comprehensive examples are provided
A review of potential-derived charges may be found in Reviews of
Computational Chemistry, Vol. II, pp. 219-271 (1991). For further
information contact Dr. Donald E. Williams, Department of Chemistry,
University of Louisville, Louisville, Kentucky 40292, USA.
Tel:(502)588-5975 Fax:(502)588-8149 E-mail:dewill01 $#at#$ ulkyvx.louisville.edu
-----------------------------------------------------------------------
Ordering information
Program package consisting of manuals, Fortran-77 source files,
and demonstration example files....................................$2,000
Special discount price is available to academic institutions ........$495
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Dear Marty,
To calculate the torsional energy barrier of a system like acetophenone
with semiempirical or ab initio methods is not so difficult since the low
energy rotational isomer probably (however see below) has a c-c-C=O torsional
angle = 0 deg (where c = aromatic carbon and C = non aromatic carbon atom) and
the high energy rotational isomer is almost certainly at 90 degrees
(perpendicular rotational isomer). In principle, one only needs to geometry
optimize both rotational isomers (holding the c-c-C-C torsional angle fixed of
course in the Z-matrix). Then one simply takes the difference in energy of these
two conformers as the torsional energy barrier. If the minimum is not at zero
degrees and/or the maximum is not at 90 degrees, it gets more complicated.
To be on the safe side, it is better to calculate the energies at
torsional angles of 0, 15, 30, 60, 75, and 90 degrees and then plot energy
versus the torsional angle (by symmetry one also has the -30, -15, 105, 120,
150, 165, and 180 torsional energies and these can be included in the plot).
A spline fit of the plot using one of many statistical graphics packages for
PC's or Mac will produce a curve. The top of the curve should be at 90
degrees and the bottom at 0 degrees. If either appears displaced from these
values, take the apparent minimum or maximum from the plot, set the torsional
angle of your starting geometry to that value, and do a complete energy
minimization in the case of the torsional minimum or a "transition-state"
optimization in case of the torsional maximum.
Again, for simple systems like acetophenone, it is usually safe to assume
that the maximum is at 90 degrees. The minumum however may be displaced from
zero degrees. To check this possibility it is best to displace the structure
slightly from zero degrees and minimize. The reason for this displacement and
extra mimimization is that many minimizers get "stuck" on planar structures
even though the minima may be non-planar. This applies to all techniques,
molecular mechanics included.
If you would like to use molecular mechanics to examine this system, and
one wants to do a careful job, one should use a method like MMP2 which will
modify the bond order of a conjugated system as a function of the torsional
angle. Finally, most standard molecular mechanics methods like MM2 contained
in MacroModel 4.0 (Clark Still, Columbia University) generally don't do too
bad a job in estimating these torsional barriers, since MacroModel MM2 at
least has been parameterized for these types of systems. MacroModel produces
a barrier of 5.81 kcal/mole for acetophenone which seems reasonable. If one
wants accurate estimates of these barriers, one should however use high level
ab initio calculations (6-31G* at least).
Finally, I am somewhat interested in your modeling of the nictotinic acetyl
choline receptor since we have previously developed a pharmacophore model of
the muscrinic M2 receptor and I have a long standing interest in ion channels.
In addition, Lynn Jelinski of Bell Labs studied the binding of acetyl choline
to the nictotinic receptor using transfer NOE techniques where the free acetyl
choline retains a memory of its bound conformation. However when we analyzed
the conformation they claimed as being the active one, it was so high in
energy, it was implausible. Someone should really go back and re-exaine that
data with a careful modeling study.
One additional point: We have developed some software called APOLLO (1-4)
(Automated PharmacOphore Location through Ligand Overlap) which might be
useful for your modeling study. Basically the program searches for low energy
conformers of ligands which allow good overlap of pharmacophore point and
therefore would "explain" the binding of a set of ligands to a common
receptor. We have already used this software to develope pharmacophore
models/active conformation hypotheses for the muscarinic receptor (1), NMDA
agonists and antagonists (2-4), as well as the benzodiazepine receptor (5).
The software works best in conjunction with MacroModel. If you have
MacroModel you might be interested in using our program. If so, let me know
and I will send you a copy. It currently runs on a VAX, but I am in the midst
of porting it to Unix. The port should be completed in a couple of weeks.
Sincerely,
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(1) Koehler, K. F.; Spangler, D. P.; Snyder, J. P. Pharmacophore
Identification through Molecular Similarity. Division of Computers in
Chemistry Computational Graph Theory and Combinatorics; Molecular Similarity
Poster Session Tuesday, September 27 Poster #35. 196th American Chemical
Society National Meeting, September 27; American Chemical Society: Los
Angeles, CA, 1988.
(2) Snyder, J. P.; Koehler, K. F.; Spangler, D. P. Searle R & D Group Employs
Receptor Mapping as a Prelude to Drug Design. Chem. Design Auto. News
1989, 4, 1.
(3) Snyder, J. P.; Rao, S. N.; Koehler, K. F.; Pellicciari, R. Drug Modeling
at Cell Membrane Receptors:the Concept of Pseudoreceptors In Trends in
Receptor Research; Angel, P.; Gulini, U. and Quagli, W., Eds.; Elsevier:
Amerdam, 1992; pp 367-403.
(4) Snyder, J. P.; Rao, S. N.; Koehler, K. F.; Vedani, A.; Pellicciari, R.
APOLLO Pharmacophores and the Pseudoreceptor Concept In Trends in QSAR and
Molecular Modeling; Wermuth, C. G. and Rival, Y., Eds.; Elsevier:
Amsterdam, 1993; pp in press.
(5) Diaz-Arauzo, H.; Koehler, K. F.; Hagen, T. J.; Cook, J. M. Synthetic and
Computer Assisted Analysis of the Pharmacophore for Agonists at
Benzodiazepine Receptors. Life Sciences 1991, 49, 207-216.
To answer the request for dihedral angle energy barriers:
The following reference is a good place to start.
It will lead you many other references with respect
to dihedral angle energy barriers of MM2 as compaired
to variable temp. NMR studies for small amines.
Brown, J. H.; Bushweller, C. H.; J. Am.
Chem. Soc. 1992, 114, 8153
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