Hello,<br>I'm very happy that so many people contributed to the subject of the (in)validity of using G53a6 for alpha helical proteins.<br>Thank you for the links.<br>I know now that I certainly should use a different force field from the GROMOS96 family, which maintains alpha helices where they should be and there are tested parameters for the lipid of my choice, POPC. I could merge lipid.itp with this force field's files and use a ready topology - that's one option...<br>
<br>Christopher<br><br><br><br><div class="gmail_quote">2010/1/21 Tsjerk Wassenaar <span dir="ltr"><<a href="mailto:tsjerkw@gmail.com">tsjerkw@gmail.com</a>></span><br><blockquote class="gmail_quote" style="border-left: 1px solid rgb(204, 204, 204); margin: 0pt 0pt 0pt 0.8ex; padding-left: 1ex;">
Hi,<br>
<br>
Well, we have compared the G53a5/6 force field with the 43a2 one and<br>
found consistently larger radii of gyration and higher RMSDs,<br>
suggesting decreased stability. There's a thorough account of it in my<br>
thesis (<a href="http://dissertations.ub.rug.nl/FILES/faculties/science/2006/t.a.wassenaar/04emb_c4.pdf" target="_blank">http://dissertations.ub.rug.nl/FILES/faculties/science/2006/t.a.wassenaar/04emb_c4.pdf</a>)<br>
and it's been published in JPCB in 2007 (DOI: 10.1021/jp068580v).<br>
<br>
Cheers,<br>
<br>
Tsjerk<br>
<div><div></div><div class="h5"><br>
On Thu, Jan 21, 2010 at 2:24 PM, XAvier Periole <<a href="mailto:x.periole@rug.nl">x.periole@rug.nl</a>> wrote:<br>
><br>
> The instability of helices with the G53a6 force field is definitely real<br>
> and unfortunately not documented. Some people are working on it ...<br>
><br>
> I would advise to be very carefull in interpreting results with this FF.<br>
><br>
> XAvier.<br>
><br>
> On Jan 21, 2010, at 2:13 PM, Justin A. Lemkul wrote:<br>
><br>
>><br>
>><br>
>> Krzysztof Mlynarczyk wrote:<br>
>>><br>
>>> 2010/1/21 Justin A. Lemkul <<a href="mailto:jalemkul@vt.edu">jalemkul@vt.edu</a> <mailto:<a href="mailto:jalemkul@vt.edu">jalemkul@vt.edu</a>>><br>
>>> Krzysztof Mlynarczyk wrote:<br>
>>> 2. If not, is there any way to derive the proper parameters for<br>
>>> the force field of my choice using the lipid parameters from<br>
>>> Peter Tieleman's website or e.g. the parameters published by<br>
>>> Andreas Kukol for G53a6?<br>
>>> I don't see why you need to do such reverse engineering. The Kukol<br>
>>> parameters for lipids under 53a6 can be directly combined with a<br>
>>> G53a6 protein without any issues; I believe that was the purpose of<br>
>>> the whole new derivation :)<br>
>>> I received a message that G53a6 is beta-sheet biased and alpha helices do<br>
>>> not perform as well as they should. My protein contains 7 transmembrane<br>
>>> helices, that's why I'm worried.<br>
>><br>
>> Is this published somewhere? That would be important information.<br>
>> Perhaps this is the case for model peptides or short fragments, but I have<br>
>> certainly done a number of simulations using 53a6 with well-folded globular<br>
>> proteins and I do not see any such instability (i.e., alpha->beta conversion<br>
>> or unwinding of alpha-helices). I do believe it is possible in certain<br>
>> scenarios, but I don't know that a large 7TM protein like yours would suffer<br>
>> adversely.<br>
>><br>
>>> I know that there are changes between parameter sets both in non-bonded<br>
>>> and bonded terms and one rtp entry will probably not work well when pasted<br>
>>> into a different force field from the same family. G96 family uses symbols<br>
>>> like gd_5 that are substituted by appropriate parameters later through the<br>
>>> use of preprocessor. While it is possible to find that gd_5 is the same as<br>
>>> gd_15 in another version of G96 and substitute those symbols in topologies,<br>
>>> the changes in non bonded parameters still can spoil what was working well<br>
>>> elsewhere. That's why I was also asking for some checked and ready-to-use<br>
>>> topologies for a particular force field.<br>
>><br>
>> Many of the bonded parameters carry over between force fields, but<br>
>> certainly new entries were created between 43a2 and 53a6, so yes, some<br>
>> re-working would likely be necessary. There is a lipid 43a2 parameter set<br>
>> on the User Contribution site, like I said before, I just don't know if<br>
>> there is a reference for it.<br>
>><br>
>>> As an aside, you are quite right that multiple force fields within<br>
>>> the same simulation is incorrect. However, the Berger lipid<br>
>>> parameters may be an exception to this rule, since they are really a<br>
>>> hybridized version of OPLS-UA and Gromos87 parameters (some of which<br>
>>> were modified anyway), so they really don't belong to any one<br>
>>> particular force field. The Berger/G87 combination is widely used,<br>
>>> but essentially amounts to the following: lipid interactions are<br>
>>> Berger-Berger or OPLS-OPLS interactions, while protein-lipid<br>
>>> interations are Berger-G87, and protein-protein interactions are<br>
>>> G87-G87. You can see quite quickly why things become complicated!<br>
>>> Based on a discussion I had with Dr. Tieleman, it seems to be<br>
>>> reasonable to use the G96 parameter set of your choice in<br>
>>> conjunction with lipid.itp (Berger lipids), although other<br>
>>> approaches may be more rigorously correct (pure G96 parameters such<br>
>>> as those by Kukol, pure OPLS recently derived by Ulmschneider, or<br>
>>> the modifications to the Berger parameters from the Tieleman group,<br>
>>> to name a few). If you want to use a G96-lipid.itp combination, I<br>
>>> created a tutorial that teaches you how to build the system and<br>
>>> properly prepare the topology. It is linked from the Tutorials page<br>
>>> of the Gromacs site.<br>
>>> I found this tutorial earlier and was also in doubt if this approach was<br>
>>> correct. But if it works, perhaps I should give it a try.<br>
>>> I gotta make a _good_ decision in the end...<br>
>><br>
>> As do we all :) My work with G53a6+Berger has thus far been quite<br>
>> reliable, from everything I can measure, but that certainly does not<br>
>> preclude the possibility (even likelihood) that there are better procedures<br>
>> out there, like those I quoted above, and certainly others (CHARMM is also<br>
>> popular for membrane proteins, but Gromacs will only *officially* support<br>
>> CHARMM as of version 4.1).<br>
>><br>
>> -Justin<br>
>><br>
>>> Christopher<br>
>><br>
>> --<br>
>> ========================================<br>
>><br>
>> Justin A. Lemkul<br>
>> Ph.D. Candidate<br>
>> ICTAS Doctoral Scholar<br>
>> MILES-IGERT Trainee<br>
>> Department of Biochemistry<br>
>> Virginia Tech<br>
>> Blacksburg, VA<br>
>> jalemkul[at]<a href="http://vt.edu" target="_blank">vt.edu</a> | (540) 231-9080<br>
>> <a href="http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin" target="_blank">http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin</a><br>
>><br>
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<br>
<br>
<br>
</div></div><font color="#888888">--<br>
Tsjerk A. Wassenaar, Ph.D.<br>
<br>
Computational Chemist<br>
Medicinal Chemist<br>
Neuropharmacologist<br>
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