Subject: Summary - VDW Collapse

From: "Hodgkin, Ed" <[email-masked]>
Date: Thu, 22 Sep 1994 15:08:58 -0500 (EST)

From: Hodgkin, Ed
Date: Thu, Sep 22, 1994 3:08 PM
Subject: Summary - VDW Collapse
To: [email-masked]
Dear CCL

A summary of replies to my "VDW Collapse" question of 2nd Sept. I think you'll 
agree there are some excellent comments. Sorry about the delay and thanks to 
everyone who replied.

PS. The replies seem to be listed in reverse order!

Edward Hodgkin
Wyeth Research (UK)
[email-masked]

Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 2:29 pm
Subject:        CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 31437120904991/454392@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: bear <MAIL1::PMDF::ellington.pharm.arizona.edu::bear>

To: NAME: chemistry <MAIL1::PMDF::ccl.net::chemistry>

Date      :  2-SEP-1994 14:29:26.00

|> From: Hodgkin, Ed
|> force fields favour 'folded' conformations

|> From: David States
|> most direct way to control for the self-association
|> of peptide chains is to do a simulation that includes 
|> solvation explicitly...

|> From: Jeff Nauss
|>Is anything similar observed with AMBER...

        In my work with solvated DNA under AMBER dynamics with
periodic boundary, water does NOT stop collapse.

bear
 
* UU  UU                SOARING BEAR                   *
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Message for Hodgkin, Ed

From:   bear
Date:   Fri, Sep 2, 1994 1:48 pm
Subject:        Re:  CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 93954120904991/454156@MAIL1

From: NAME: bear <MAIL1::PMDF::ellington.pharm.arizona.edu::bear>

To: NAME: Hodgkin, Ed <PRIN1::MRAM_PRIN1::HODGKINE>

Date      :  2-SEP-1994 13:48:51.00
        "Van Der Waals Collapse", yes, what a great term.   I've
been observing and sometimes struggling with this with our DNA
models for some time but never had such a good name for it.
        I have the feeling that it suggests further refinements
in force fields are necessary.   Restraints will prevent such
a collapse but defeat the whole purpose of mechanics and dynamics.
bear
* UU  UU                SOARING BEAR                   *
* UU  UU          Computer Aided Drug Design           *
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Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 10:30 am
Subject:        CCL:collapsing water droplets
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 05722120904991/453892@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: Heather Carlson <MAIL1::PMDF::ramana.chem.yale.edu::heather>

To: NAME: chemistry <MAIL1::PMDF::ccl.net::chemistry>

Date      :  2-SEP-1994 10:30:06.00

Just another word on simulated water droplets (spherical caps)...

During a simulation of a 12 A radius cap, we observed the compression
previously mentioned on the net.  In order to obtain the same O-O
radial distribution function in a periodic cell, we have to set the
NPT ensemble to 1500 atm.  I realize this isn't addressing the vdw
collapse, but since droplet compression was mentioned, I figured it 
would be of interest since adding an extra factor of compressiomn
would be counter-productive.

Heather Carlson
[email-masked]

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Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 8:31 am
Subject:        CCL:VDW collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 83720120904991/453730@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: Rick Loncharich <MAIL1::PMDF::Lilly.com::LONCHARICH_RICHARD_J>

To: NAME: chemistry <MAIL1::PMDF::ccl.net::chemistry>

Date      :  2-SEP-1994 08:31:15.00
|> From: Hodgkin, Ed
|> 
|> It is well known that molecular mechanics force fields favour 'folded' 
|> conformations which derive stability from large Van Der Waals terms. 
|> One could coin the phrase "Van Der Waals Collapse" to describe this 
|> effect....

|> From: David States
|> . . .  The most direct way to
|> control for the self-association of peptide chains is to do a
|> simulation that includes solvation explicitly.  Note that if you do
|> this as a water droplet rather than a periodic box the internal
|> pressure generated by surface tension is enormous so the system will
|> still collapse some compared to physiologic conditions.

Furthermore, as one increases the amount of water in a water droplet 
simulation from 0 to 4000 water molecules the size of the protein 
(measured by rgyr) increases to the X-ray radius of gyration.  See
recent articles by B.R. Brooks et. al.

Rick Loncharich
Eli Lilly and Company

From: LONCHARICH RICHARD J          (MCVAX0::RX82788)

To:   FOREIGN TRANSPORT ADDRESSEE   (MCDEV1::IN%"[email-masked]")

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Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 8:11 am
Subject:        CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 61620120904991/453724@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: nauss <MAIL1::PMDF::ucmod2.che.uc.EDU::nauss>

To: NAME: CHEMISTRY <MAIL1::PMDF::ccl.net::CHEMISTRY>

Date      :  2-SEP-1994 08:11:17.00
>From: [email-masked] (David J. States)

>|> From: Hodgkin, Ed
>|> 
>|> It is well known that molecular mechanics force fields favour 'folded' 
>|> conformations which derive stability from large Van Der Waals terms. 
>|> One could coin the phrase "Van Der Waals Collapse" to describe this 
>|> effect....
>
>From the earliest days of charmm development, this has been a concern.
>Globular proteins simulated in vacuo shrink when "true" atomic radii
>are used as the basis for nonbonded interaction parameters...
>The most direct way to
>control for the self-association of peptide chains is to do a
>simulation that includes solvation explicitly.

I observed this phenomenon when I was running CHARMM a couple years
ago.  However, it does not appear to be a major problem with Biosym's
Discover using the CVFF forcefield.  I emphasis the word major as I do
observe some collapse of proteins and peptides but never to the extent
that CHARMM produced.

Anyone have any comments on the difference between the two forcefields
and this "Van Der Waals Collapse?"  Is anything similar observed with
AMBER or GROMOS?

                                                Jeff Nauss

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*  UU    UU             Jeffrey L. Nauss, PhD                              *
*  UU    UU             Director, Molecular Modeling Services              *
*  UU    UU             Department of Chemistry                            *
*  UU    UU CCCCCCC     University of Cincinnati                           *
*   UU  UU CCCCCCCC     Cincinnati, OH 45221-0172                          *
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Message for Hodgkin, Ed

From:   gregory
Date:   Fri, Sep 2, 1994 4:29 am
Subject:        Re:  CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 95610120904991/453716@MAIL1

From: NAME: gregory <MAIL1::PMDF::wucmd.wustl.edu::gregory>

To: NAME: Hodgkin, Ed <PRIN1::MRAM_PRIN1::HODGKINE>

Date      :  2-SEP-1994 04:29:28.00
 There are basically two separate problems with atom-atomic energy calculations.
 One is for large molecules (proteins). Any estimations of intramolecular
 energy are just estimations. In other words, if you have an error of 0.0001%
 in estimation of every individual atom-atomic interaction (say, Ecalcd = 0.25
 kcal/mol instead of the "real" 0.2500025 value), you will need about 1,000
 atoms interacting with each other, to get an overall error of 100%. (O.K.,
 there might be some compensatory effects; let us suggest 2,000 atoms.) This
 means that any energy estimations in large system would not give you a correct
 energy value. Therefore, any efforts spent on molecular mechanics calculations
 of proteins cannot, generaly speaking, reach their goals. Accordingly, you
 do not need to worry about the "vdW" collapse in this case.

 Small molecules (peptides) are different. Here you can count on your energies,
 at least you can safely pick out those inside some enrgy threshold (but do
 not think, that that with E = 1.5 kcal/mol is really better than that of
 4.5 kcal/mol; considering the inevitable errors involved, they are equal).
 My experience with the ECEPP is that up to hexa/heptapeptide you will always
 have a large variety of folded/extended 3D structures among your low-energy
 (i.e., those with energies less than detlaE) conformers. Moreover, the
 averaging (of special sort) over these conformers will give you a good
 agreement with an experiment in solution. As to the conformers binding to
 receptors, all our models (proved by experiment) were folded conformers.
 However, if you follow the rule of keeping ALL low-energy conformers as
 possibilities, you will keep the extended conformers (like that of protease
 substrates) as well.

 In other words: you cannot solve the "vdW" collapse problem, but you can
 obtain the correct results by taking into account all (or as close to all as
 you can) low-energy conformers for your system.

 Good luck.

 Gregory Nikiforovich

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Message for Hodgkin, Ed

From:   Julian Tirado-Rives
Date:   Fri, Sep 2, 1994 8:38 am
Subject:        Re: CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 64149020904991/453575@MAIL1

From: NAME: Julian Tirado-Rives <MAIL1::PMDF::matrix.chem.yale.edu::julian>

To: NAME: HODGKINE <PRIN1::MRAM_PRIN1::HODGKINE>

Date      :  2-SEP-1994 08:38:49.00
> 
> From: Hodgkin, Ed
> Date: Fri, Sep 2, 1994 9:30 AM
> Subject: Van Der Waals Collapse
> To: [email-masked]
> Dear All
> 
> It is well known that molecular mechanics force fields favour 'folded' 
> conformations which derive stability from large Van Der Waals terms. One 
could 
> coin the phrase "Van Der Waals Collapse" to describe this effect. However I 
am 
> not aware of any published work which addresses this issue. Are there any 
> methods which compensate for the folding effect, thereby giving lower 
energies 
> for extended conformations which are probably more relevant for molecules in 
> solution or in binding sites.
> 
> I'll summarize the replies, of course.
> 
> Edward Hodgkin
> Wyeth Research (UK)
> E-mail: [email-masked]
> 

   Do you have any references for this "well known" fact?  Given that there
are published reports of unfolding proteins in solution I would be curious
to know how was the unfeasibility of this simulation stablished.

  Thanks!

    ---------------------------------------------------------------------
   |  Julian Tirado-Rives          |                                     |
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Message for Hodgkin, Ed

From:   theochem
Date:   Fri, Sep 2, 1994 8:52 am
Subject:        vdW collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 24558020904991/453481@MAIL1

From: NAME: theochem <MAIL1::PMDF::ctc.com::theochem>

To: NAME: hodgkine <PRIN1::MRAM_PRIN1::hodgkine>

Date      :  2-SEP-1994 08:52:58.00
Ed:
        A real example of this situation occurred in our papers in Tetrahedron
Letters in which we studied the conformations of Gellman's amides using the
MacroModel AMBER force field. Our results overestimated the contribution of
the seven-membered ring hydrogen bonded conformation relative to the 9 and 6
conformations. Clark Still then reparameterized AMBER and announced AMBER*,
which included some new torsional terms to correct for this problem. 

        Just shortly after we published our modeling results, Mike Whang-bo
published a semiempirical study of the same systems and came to the same
conclusions. So something in MOPAC/AM1 also lead to an overestimation of
the 7-membered ring. This may be an artifact due to the use of gaussian 
functions in the semiempirical paramterization, but J. Stewart or A. Holder
would be more appropriate sources of information on that.

        I do not have all my references handy because of my recent move to
CTC, but my papers appeared in Tet. Letters 1991, 32, 3613-6 and 3617-20. 
Sam Gellman had a response in Tet. Letters late in the same year or early
the next year; Still's paper (I believe that Quentin McDonald is the lead
author) appeared at the end of 1991 or 1992 in TL as well. Whang-bo's work
appeared in JACS early in 1992 (I believe).

Doug
-- 

Douglas A. Smith
Theoretical Chemist
Concurrent Technologies Corporation
1450 Scalp Avenue
Johnstown, PA 15904

voice:  (814) 269-2545
fax:    (814) 269-2798
email:  [email-masked]  !!!NEW!!!

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and still:

Douglas A. Smith                        voice:  N/A
Associate Professor                     fax:    N/A
Department of Chemistry                 email:  [email-masked]
 and
Center for Drug Design and Development
The University of Toledo
Toledo, OH  43606-3390

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Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 7:19 am
Subject:        CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 84748020904991/453460@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: states <MAIL1::PMDF::ibc.wustl.edu::states>

To: NAME: HODGKINE <PRIN1::MRAM_PRIN1::HODGKINE>

To: NAME: chemistry <MAIL1::PMDF::ccl.net::chemistry>

Date      :  2-SEP-1994 07:19:12.00
|> From: Hodgkin, Ed
|> 
|> It is well known that molecular mechanics force fields favour 'folded' 
|> conformations which derive stability from large Van Der Waals terms. 
|> One could coin the phrase "Van Der Waals Collapse" to describe this 
|> effect....

From the earliest days of charmm development, this has been a concern.
Globular proteins simulated in vacuo shrink when "true" atomic radii
are used as the basis for nonbonded interaction parameters.
Swaminathan spent alot of time working on a compensating force term,
but I don't know what became of the work.  The most direct way to
control for the self-association of peptide chains is to do a
simulation that includes solvation explicitly.  Note that if you do
this as a water droplet rather than a periodic box the internal
pressure generated by surface tension is enormous so the system will
still collapse some compared to physiologic conditions.

David States

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Message for Hodgkin, Ed

From:   MARYJO
Date:   Fri, Sep 2, 1994 7:39 am
Subject:        Re: CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 92047020904991/453316@MAIL1

From: NAME: MARYJO <MAIL1::PMDF::neu.edu::MARYJO>

To: NAME: HODGKINE <PRIN1::MRAM_PRIN1::HODGKINE>

Date      :  2-SEP-1994 07:39:52.00
Hello Edward.

It is my opinion that van der Waals collapse should be observed
if large molecules can be released to the gas phase and probed.
I believe that the unfair favoritism of folded structures in the
condensed phase is a simple consequence of inadequate treatment
of intermolecular forces, in many cases.  The often excluded
molecule-solvent and intermolecular forces between neighboring
molecules will compete with intramolecular forces.  Many
standard modelling software packages do not automatically
incorporate these competing forces, and thus folded structures
prevail.

Mary Jo Ondrechen

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Message for Hodgkin, Ed

From:   chemistry-request
Date:   Fri, Sep 2, 1994 9:30 am
Subject:        CCL:Van Der Waals Collapse
To:     Hodgkin, Ed
File(s):        Attach.Txt1

Regarding Message ID : 00216020904991/453268@MAIL1

From: NAME: chemistry-request <MAIL1::PMDF::ccl.net::chemistry-request>

Author: NAME: Hodgkin, Ed <PRIN1::MRAM_PRIN1::HODGKINE>

To: NAME: [email-masked] <MAIL1::PMDF::ccl.net::chemistry>

Date      :  2-SEP-1994 09:30:15.00
From: Hodgkin, Ed
Date: Fri, Sep 2, 1994 9:30 AM
Subject: Van Der Waals Collapse
To: [email-masked]
Dear All

It is well known that molecular mechanics force fields favour 'folded' 
conformations which derive stability from large Van Der Waals terms. One could 
coin the phrase "Van Der Waals Collapse" to describe this effect. However I am 
not aware of any published work which addresses this issue. Are there any 
methods which compensate for the folding effect, thereby giving lower energies 
for extended conformations which are probably more relevant for molecules in 
solution or in binding sites.

I'll summarize the replies, of course.

Edward Hodgkin
Wyeth Research (UK)
E-mail: [email-masked]

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