[gmx-users] Force-field bias???

Thu Aug 6 22:55:26 CEST 2015

On Wed, 5 Aug 2015, Justin Lemkul wrote:

>
>
> On 8/5/15 10:32 AM, Smith, Micholas D. wrote:
>> OPLS-AA 2001 (the one implimented in gromacs) can be a little slow in 
>> folding
>> (in both my experience, and from   doi:10.1016/j.bpj.2009.04.061 ). That is
>> not necessarily a bad thing if the peptide is suppose to take a while to
>> fold. If you just want to get to the folded structure, and you don't care
>> about the pathway, you could also use an enhanced sampling technique.
>> 
>> An alternative force-field that seems to handle beta structures pretty 
>> well,
>> but can sometime accelerate the folding is the older GROMOS53A force-field;
>> though since it is united atom, I have found that sometime the contacts 
>> don't
>> quite match with NMR data.
>> 
>
> Beware, it's well known that 53A6 systematically under-stabilizes helices 
> such that you get inappropriate unfolding.  It samples the unfolded state 
> quite well, but again, this may be application-specific.

That under-stabilization of helices in 53A6 seems to have been mostly 
solved by the few changes that led to 54A7, which is able to reproduce 
both the thermodynamics and the kinetics of helix formation in a cyclic 
peptide model (doi: 10.1021/ct400529k). So, I would say that 54A7 is 
largely a "fixed" 53A6 in that respect (plus a few changes on choline 
groups and ions).

Of course, the fact that the kinetics seems good is not necessarily a good
thing if you just want thermodynamics (relative populations), because
sampling may turn out to be too slow for your system... or not...

Best,
Antonio

--
Antonio M. Baptista
Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa
Av. da Republica - EAN, 2780-157 Oeiras, Portugal
phone: +351-214469619         email: baptista at itqb.unl.pt
fax:   +351-214411277         WWW:   http://www.itqb.unl.pt/~baptista
--------------------------------------------------------------------------

>
> -Justin
>
>> Force-field choice is a non-trival, but largely difficult problem to deal
>> with. In general, though, I tend to avoid the older Amber force-fields when
>> simulating beta-rich peptides as have had a bias towards helical structures
>> (see the references within the paper I noted above).
>> 
>> Good Luck,
>> 
>> Micholas
>> 
>> =================== Micholas Dean Smith, PhD. Post-doctoral Research
>> Associate University of Tennessee/Oak Ridge National Laboratory Center for
>> Molecular Biophysics
>> 
>> ________________________________________ From:
>> gromacs.org_gmx-users-bounces at maillist.sys.kth.se
>> <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of SAPNA 
>> BORAH
>> <sapnauser365 at gmail.com> Sent: Wednesday, August 05, 2015 10:20 AM To:
>> gmx-users at gromacs.org Subject: Re: [gmx-users] Force-field bias???
>> 
>> Dear all,
>> 
>> Thank you for your answers which definitely clears some of my doubts. I am
>> trying to unfold a lectin tetramer protein that comprises largely of beta
>> strands, and I have used the OPLS ff, so far I have not been successful, 
>> can
>> OPLS be a problem at all??
>> 
>> Thanks..
>> 
>> Sapna Mayuri Borah c/o Dr. A. N. Jha Research student Tezpur University,
>> India
>> 
>> On Wed, Aug 5, 2015 at 5:44 PM, Smith, Micholas D. <smithmd at ornl.gov> 
>> wrote:
>> 
>>> You should also note that force-field bias may be system dependent. So if
>>> you are unsure of the dynamics from the onset, you should likely test a
>>> variety of force-fields and/or try to find a comparison to NMR (or other)
>>> experimental methods.
>>> 
>>> -Micholas
>>> 
>>> =================== Micholas Dean Smith, PhD. Post-doctoral Research
>>> Associate University of Tennessee/Oak Ridge National Laboratory Center for
>>> Molecular Biophysics
>>> 
>>> ________________________________________ From:
>>> gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
>>> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Justin
>>> Lemkul <jalemkul at vt.edu> Sent: Wednesday, August 05, 2015 7:31 AM To:
>>> gmx-users at gromacs.org Subject: Re: [gmx-users] Force-field bias???
>>> 
>>> On 8/5/15 6:24 AM, SAPNA BORAH wrote:
>>>> Dear all,
>>>> 
>>>> I have a general query about unfolding simulations. Is there a bias
>>>> among force-fields selected for unfolding, i.e. is it possible that
>>>> unfolding
>>> of
>>>> the protein may be different with a change in force fields applied?
>>>> Literature has given some support on this, however, I am not sure how
>>> this
>>>> may happen.
>>>> 
>>> 
>>> Yes, this is true.  It usually comes down to errors in the balance between
>>> intra-protein and protein-water interactions.  Incorrect balance favors
>>> either the folded or unfolded state.  No force field is perfect, but some
>>> are better than others and there's lots of literature on this topic
>>> regarding which are the most successful.
>>> 
>>> -Justin
>>> 
>>> -- ==================================================
>>> 
>>> Justin A. Lemkul, Ph.D. Ruth L. Kirschstein NRSA Postdoctoral Fellow
>>> 
>>> Department of Pharmaceutical Sciences School of Pharmacy Health Sciences
>>> Facility II, Room 629 University of Maryland, Baltimore 20 Penn St.
>>> Baltimore, MD 21201
>>> 
>>> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
>>> http://mackerell.umaryland.edu/~jalemkul
>>> 
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>
> -- 
> ==================================================
>
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
>
> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
>
> ==================================================
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