Re: accelerated MD as the engine for loop refirement

From: James Starlight (jmsstarlight_at_gmail.com)
Date: Sun Jul 13 2014 - 14:05:10 CDT

oh sorry it was quite difficulte to send message from the mobile phone :-)
 so I'd to specify my question.

1 )Regardless of the enhansed sampling method I wounder if the simulation
of membrane protein in principle will be possible placing the protein
within the water box (not into the membrane) and with the application of
the restraints on its all atoms (to prevent its unfolding due to its
contact with the water not with the membrane) apart from the loops which
should be refined (which are in both cases will be accesible to water)?

2) Had someone been experienced with the rosetta package for loop modelling
in case of membrane proteins? On what general ideas such refirement is
based?

James

2014-07-12 18:28 GMT+04:00 James Starlight <jmsstarlight_at_gmail.com>:

> Thanks alot!
>
> Some additional question:
>
> Assuming that I need to refine loops quickly of my membrane receptor what
> should be expected if I 1) place the whole protein into the water box (no
> membrane) 2) apply position restraints onto the all parts of this protein
> which in fact must be embedded into the membrane to artifacts of its
> contact with water (not membrane) in my model 3) run some enhansing
> sampling engine to sample loops only in water box keeping all other parts
> frozen. Could some artifacts in loops be arrise due to such coarse-graining
> of the environment?
>
> James
>
>
> 2014-07-11 2:59 GMT+04:00 Gianluca Interlandi <gianluca_at_u.washington.edu>:
>
> Why not just running accelerated MD and explicit solvent? That might
>> already confer an idea of the flexibility of the loops. Another alternative
>> is to use metadynamics (implemented as COLVARS in NAMD or through the
>> plumed plugin) and explicit water. Metadynamics should be more efficient
>> than accelerated MD once you have identified the correct collect variables.
>>
>> You can also try out implicit solvent on its own or couple it with REM.
>> But I would always test those things independently before combining them.
>>
>> Gianluca
>>
>>
>> On Thu, 10 Jul 2014, Kenno Vanommeslaeghe wrote:
>>
>> It all depends. These loops often require very long timescales to get
>>> descent sampling, such that the sampling error when using explicit solvent
>>> might be greater than the error in the implicit solvent energetics. Though
>>> I have no idea whether there's any specific crosstalk between Accelerated
>>> MD and implicit solvent (my guess would be "no" but that's just a guess).
>>>
>>>
>>> On 07/09/2014 04:08 PM, Gianluca Interlandi wrote:
>>>
>>>> Accelerated MD + implicit solvent. In my opinion, that might cause too
>>>> many distortions. It's a good start to get an idea of the accessible
>>>> phase
>>>> space but whether that will really tell you the most likely conformation
>>>> nobody can say for sure. I would use regular MD in explicit solvent
>>>> coupled with something like REM. But that is just my 2c.
>>>>
>>>> A good start would be to simply run two MD simulations in explicit water
>>>> at 300 and/or 310 K (50 - 100 ns) and see what those loops do.
>>>>
>>>> Gianluca
>>>>
>>>> On Wed, 9 Jul 2014, James Starlight wrote:
>>>>
>>>> Dear NAMD users!
>>>>>
>>>>> I wounder whether the accelerated molecular dynamics might be good
>>>>> solution for the
>>>>> loop refirement of models made by means of hoology modeling with the
>>>>> teplated which
>>>>> has the low sequence identify in loop region? For instance I've just
>>>>> built some
>>>>> models of membrane receptors agains receptor with known structures and
>>>>> would like to
>>>>> refine loops by some enhansed sampling engine to sample all possible
>>>>> conformation and
>>>>> found most propable during short simulation. Does the acceleraed md
>>>>> good
>>>>> sollution
>>>>> for such task assuming simulation with implicit solvent with restrained
>>>>> all atoms of
>>>>> the helix regions of the refined protein but not loops flexible region?
>>>>> What
>>>>> alternatives should I explored also?
>>>>>
>>>>> TFH,
>>>>>
>>>>>
>>>>> James
>>>>>
>>>>>
>>>>>
>>>> -----------------------------------------------------
>>>> Gianluca Interlandi, PhD gianluca_at_u.washington.edu
>>>> +1 (206) 685 4435
>>>> http://artemide.bioeng.washington.edu/
>>>>
>>>> Research Assistant Professor at the Department of Bioengineering
>>>> at the University of Washington, Seattle WA U.S.A.
>>>> -----------------------------------------------------
>>>>
>>>>
>>>
>>>
>> -----------------------------------------------------
>> Gianluca Interlandi, PhD gianluca_at_u.washington.edu
>> +1 (206) 685 4435
>> http://artemide.bioeng.washington.edu/
>>
>> Research Assistant Professor at the Department of Bioengineering
>> at the University of Washington, Seattle WA U.S.A.
>> -----------------------------------------------------
>>
>>
>

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