[gmx-users] Urea induced denaturation and urea force fields.

[Mark Abraham]

Hi,

Knowing whether things like urea diffusion constants are modelled well
would have been good preliminary studies / lit review. Otherwise, as
Krzyszstof suggests, you've probably just done a desorption study. But come
up with an estimate of the rate of adsorb/desorb events before you try
another simulation ;-)

Mark

On Mon, 28 Mar 2016 17:49 Krzysztof Kuczera <kkuczera at ku.edu> wrote:

> Hi
> I think the reason your urea molecules moved away from the protein is
> the concentration gradient introduced through your solvation scheme  -
> since [urea] = 0 in the bulk, we can expect the molecules to
> spontaneously diffuse there. Probably solvating with an equilibrated
> water+urea box with high urea concentration would work better - see
> how-to's section of gromacs  website  for using mixed solvents
> Krzysztof
>
> On 3/25/16 10:34 PM, Sagar Khavnekar wrote:
> > Dear Gromacs Users,
> >
> > I have some questions about MD simulations we performed following our
> > crystallographic investigations into urea induced denaturation.
> >
> > We have performed some crystallographic experiments to capture initial
> > phases of urea induced denaturation of HEWL.
> >
> > We have observed initial changes in protein structure such as breaking of
> > structurally important h bonds as a result of urea binding. We further
> > wanted to see if similar structural alterations occur when we simulate
> > native structure in the presence of these urea molecules, the positions
> of
> > which are taken from the crystal structure.
> >
> > hence we prepared a starting system as follows
> >
> > we superposed native structure onto HEWL structure from the urea complex.
> > Hence in starting system HEWL is in native conformation along with urea
> > molecules which are observed in the case of complex.
> >
> > we solvated this starting system in tip3p water and performed energy
> > minimization. we had restrained urea molecules during equilibration. for
> > production MD we removed these restrains onto urea molecules. it was
> > observed that urea molecules fly away from their positions soon after
> > starting production MD.
> >
> > hence we restrained urea molecules in order to see local changes that
> these
> > urea molecules will bring out in the native structure if they are present
> > at crystallographically observed positions. I would like to get opinions
> > from the gromacs community about this approach of restraining urea
> > molecules for observation of local dynamics or for observation of
> possible
> > conformational transition from native HEWL to the one in complex with
> urea.
> >
> > Now the question that has come up after review of our manuscript is that
> > aret these retrains introducing crystallographic artifacts into MD.
> >
> > Another question is if urea molecules are flying off then is it due to
> > force field that might be biased by many solution studies which suggest
> > that urea denatures by weak interactions in contrast to strong
> interactions
> > such as we have observed in our crystallographic study. for the purpose
> of
> > information resolution of our structures is 1.6 Ang.
> >
> > Another thing I would like to have experts opinion about is as follows.
> >
> > In our opinion the best thing to do MD without restraining urea molecules
> > will be to simulate nanocrystal spanning few unit cells in 9M urea/ But
> it
> > will be computationally expensive. We do not have enough computing power
> to
> > carry out such a massive simulation. Hence, will it be sensible to say we
> > didn't do it due to lack of computing power?
> >
> > further most of MD simulations start from Protein molecule in mixed
> solvent
> > of water and urea. but in reality when you dissolve protein in 9 molar
> urea
> > protein has its solvation shell around itself. Hence isnt it better to
> > perform denaturation simulation starting from hydrated protein with few
> > hydration shells around it? and if we do so are present force fields able
> > to account for urea water diffusion, especially the penetration of urea
> > into hydration shell of protein?
> >
> > PS we used amber 99 ildn
> >
>
>
> --
> Krzysztof Kuczera
> Departments of Chemistry and Molecular Biosciences
> The University of Kansas
> 1251 Wescoe Hall Drive, 5090 Malott Hall
> Lawrence, KS 66045
> Tel: 785-864-5060 Fax: 785-864-5396 email: kkuczera at ku.edu
> http://oolung.chem.ku.edu/~kuczera/home.html
>
> --
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