Re: AMBER: GB versus explicit medium

From: Francesco Pietra <>
Date: Mon, 24 Nov 2008 16:33:43 +0100

On Mon, Nov 24, 2008 at 12:08 PM, Carlos Simmerling
<> wrote:
> Using GB to replace explicit water already has some weaknesses, but I
> think GB with dielectric of ~80 is an even worse model for the
> interior of a lipid..
> I'm not sure if that is the problem, but I would not really expect
> this to work. Charlie Brooks has used his GB for membranes, but they
> define a dielectric boundary at the water/lipid interface. There is a
> review article on this in ARCC.

I'll look for the article, it would help if you have the exact ref.

Actually, my initial plan was to embed the pore region into a hydrated
POPC membrane and define GB for the extracellular part. I first tried
GB for the whole, getting discouraged by the high computational cost.
Adding the membrane it would be to much, or too costly. Finally, given
the nature of the protein, with so many variables for the status of
the amino acids (in the GB simulation the protein has a charge -50!
and the best pKa simulation programs are defeated by so much stuff: I
tried) this is a project for the future, or for unlimited
computational resources. Unless Charlie Brooks' methodology is (for
me) computationally affordable, I am forced to to leave docking to the
extracellular part at the status that the docking program was able to
do; it works through a huge number of reciprocal orientations but the
proteins are left to their crystallographic conformations. Certainly
not the best model since the crystallographic data are at a very low
temperature. I would be happy enough to be able to pave the way for
future research.

I agree that there may be a bias overriding the capability of GB. I
tried to be careful with the steps preceding production, following
advice that you kindly provided before (notice that there was no
protein distortions before MD production; distortion - as described -
came out slowly and gradually during production). How production is
carried out in steps was outlined in my previous mail.


> in order to make the GB vs explicit comparison that you did below, you
> really need to compare the same system, not a comparison where ones
> has many more restraints.
> On Mon, Nov 24, 2008 at 4:39 AM, Francesco Pietra <> wrote:
>> Hi all:
>> Is any experience in carrying out long MD simulations for
>> transmembrane proteins under both GB conditions and explicit
>> environment?
>> This question because I am carrying out MD with a large transmembrane
>> protein, composed of several identical units and carrying a docked
>> small protein (docked in accordance with physiological data) in the
>> extracellular part. MD under GB conditions after a careful
>> minimization and heating to 300K. Force field ff99SB.
>> MD under GB at 300K
>> with restraint on Cl-
>> using pmemd in amber10
>> &cntrl
>> imin=0, irest=1, ntx=5, ntb=0,
>> ig=-1, igb=5, nrespa=2, ntc=2,
>> ntf=2, ntt=3, gamma_ln=2.0,
>> nstlim=30000, dt=0.002,
>> ntpr=100, ntwx=100,
>> tempi=300.0, temp0=300.0,
>> cut=999.0, rgbmax=999.0,
>> ntr=1,
>> /
>> Keep Cl- 427 restrained
>> 32.0
>> RES 427
>> END
>> END
>> I understand that, forced by the huge system, I am using rather
>> drastic conditions (dt=0.002, nrespa=2), though I was badly surprised
>> to see the initial portion of one of the chains of the pore region
>> undergoing a 90 degrees bent at SER 14 (14 from the beginning of the
>> chain, while the chain continues for ca 23 amino acids in the pore
>> region). EPTOT EKTOT and ETOT remain constant. The extracellular
>> portion and docked small protein also undergo some conformational
>> adjustment, though, no "distortion" of the system occurs.
>> In another approach, for different reasons, I isolated the pore region
>> (with a small molecule docked in; docked in accordance with
>> physiological data)), cutting away the extracellular portion and
>> restraining the ends of the chains at the end of the pore region.
>> Under periodic conditions, in a hydrated POPC membrane, for a much
>> longer MD than the above, no distortion of the pore region occurred
>> Production MD, restraining
>> capping groups
>> &cntrl
>> imin=0, irest=1, ntx=5,
>> nstlim=100000, dt=0.002,
>> cut=10, ntb=2, ntp=1, taup=2.0,
>> ntc=2, ntf=2,
>> ntpr=1000, ntwx=1000,
>> ntt=3, gamma_ln=2.0,
>> temp0=300.0,
>> ntr=1,
>> /
>> Keep ACE 79 restrained
>> 32.0
>> RES 79
>> END
>> many other capping groups restrained.
>> I wonder whether this may be a limitation of GB or there is evidence,
>> or suspicion, that setting up was not adequate. Surely, if the GB
>> simulation has to be made some fold slower that it is, the simulation
>> could hardly be carried out for an adequate time.
>> Thanks
>> francesco pietra
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Received on Fri Dec 05 2008 - 16:34:29 PST
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