RE: accelerated MD as the engine for loop refirement

From: Tristan Croll (
Date: Mon Jul 14 2014 - 18:18:05 CDT

It would be best if I deferred to the experts on your more detailed questions. The only point I wanted to make is that with any method that adds substantial amounts of energy to your system (whether it be aMD or REMD) you’re increasing the risk of inducing non-physiological conformations. The most obvious of these is the flipping of backbone peptide bonds into the cis conformation.

From: James Starlight []
Sent: Monday, 14 July 2014 8:17 PM
To: Tristan Croll; Namd Mailing List; Jeff Wereszczynski
Subject: Re: namd-l: accelerated MD as the engine for loop refirement

Hi Tristan,

most people suggest me to use REMD instead of aMD for loop refirement because AMD might seriously alter thermodynamics of the system (during rewealling for instance). This will result in the non-physical conformations of the refined loops because of the non-bolzman distribution pattern obtained after AMD. What do you think about it? Also It'be very interested to know Jeff's opinions about such topic because of its great experiuence in this method.


2014-07-14 9:40 GMT+04:00 Tristan Croll <<>>:
If you’re going to try an accelerated MD approach like this I would recommend at the very least applying cispeptide restraints to all mobile residues (with perhaps the exception of X-Pro).

From:<> [<>] On Behalf Of James Starlight
Sent: Monday, 14 July 2014 5:05 AM
To: Namd Mailing List
Subject: Re: namd-l: accelerated MD as the engine for loop refirement

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?


2014-07-12 18:28 GMT+04:00 James Starlight <<>>:
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?


2014-07-11 2:59 GMT+04:00 Gianluca Interlandi <<>>:

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.


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.


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
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?
alternatives should I explored also?



Gianluca Interlandi, PhD<>
                     +1 (206) 685 4435<tel:%2B1%20%28206%29%20685%204435>

Research Assistant Professor at the Department of Bioengineering
at the University of Washington, Seattle WA U.S.A.

Gianluca Interlandi, PhD<>
                    +1 (206) 685 4435<tel:%2B1%20%28206%29%20685%204435>

Research Assistant Professor at the Department of Bioengineering
at the University of Washington, Seattle WA U.S.A.

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