[gmx-users] Applying restraints into 'secondary structure' of a Protein

[Carlos Navarro Retamal]

Dear Mark,
Thanks for your reply.

Does it do that in just-water also? If the structure is not rock-stable in
water, then your required minimum amount of sampling goes up immensely,
because you will have to sample many such transitions to observe adsorption
(when/if it happens).

Yes it does.
The main issue is that this proteins are intrinsically disordered proteins on water, so on water this protein moves randomly.
That’s why at first i placed the protein near to the hydrophilic interface of the POPC membrane in order to ‘force it’ to interact with it, sadly without luck. This is the reason why i’m in the need to find a way to force the protein to maintain its tertiary structure.

Looking into literature i found different papers, where the authors propose an umbrella sampling strategy in order to map the reaction coordinate of the overall process.
http://pubs.rsc.org/EN/content/articlelanding/2013/sm/c3sm51990b/unauth#!divAbstract
http://www.sciencedirect.com/science/article/pii/S0005273612002581

what do you think about this strategy?
Since i don’t have access to a big computer center,  i don’t know if i’ll be able to run this kind of simulations (I’m currently performing around ~40ns on system with about 90k - 120k atoms, and this system; POPC+water molecules+protein, is around 110k).

Thanks for your help
--
Carlos Navarro Retamal
Bioinformatics Engineering
Ph. D (c) Applied Sciences.
Center of Bioinformatics and Molecular Simulations. CBSM
University of Talca
Av. Lircay S/N, Talca, Chile
T: (+56) 712201 798
E: carlos.navarro87 at gmail.com or cnavarro at utalca.cl



On January 13, 2015 at 3:34:10 AM, Mark Abraham (mark.j.abraham at gmail.com<mailto:mark.j.abraham at gmail.com>) wrote:

On Tue, Jan 13, 2015 at 3:45 AM, Carlos Navarro Retamal <cnavarro at utalca.cl>
wrote:

> Dear gromacs users,
> In order to analyse the adsorption process of a Protein (amphipatic
> protein) into a POPC membrane i’m placing several conformations at
> different distances of respective membrane (on different simulations) and
> performed regular MD simulations.
> My problem is that during the production phase the protein start to move
> randomly, loosing its amphipatic nature (and in that way, moving far from
> the POPC hydrophobic interface).
>

Does it do that in just-water also? If the structure is not rock-stable in
water, then your required minimum amount of sampling goes up immensely,
because you will have to sample many such transitions to observe adsorption
(when/if it happens).

So, my question is: Is there a way to maintain the tertiary structure
> ('overall’) of the protein (in my particular case, two alpha helices joined
> by a loop) allowing it to maintain its amphipatic nature during the
> simulation, helping it to interact peripherally to the hydrophobic
> interface of the membrane?
>

The traditional hacks for doing this include distance and orientation
restraints between parts of your protein. Whether those mask relevant
motion is difficult to say, since you're not going to be able to afford the
calculation that shows what you'd observe if the restraints were absent (or
you'd just do it that way).

In any case, maybe this is not the ideal strategy to analyse the
> interaction between this two macromolecules (protein interacting
> peripherally with respect to a bilayer membrane), so if you think in
> something else please feel free to make any suggestions.
>

The brute-force sampling required for such a study seems to require an
amount of current resources that is impossibly large. But I don't know of
an alternative.

Mark


> Best regards,
> Carlos
> --
> Carlos Navarro Retamal
> Bioinformatics Engineering
> Ph. D (c) Applied Sciences.
> Center of Bioinformatics and Molecular Simulations. CBSM
> University of Talca
> Av. Lircay S/N, Talca, Chile
> T: (+56) 71 2 201<tel://T:%20(+56)%2071%202%20201> 798
> E: c<mailto:francisco.adasme at gmail.com>arlos.navarro87 at gmail.com or
> cnavarro at utalca.cl<mailto:fadasmec at utalca.cl>
>
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