AMBER: Protein dynamics.

From: Laurence Lavelle <>
Date: Tue, 07 Jun 2005 22:52:00 -0700

Both David and Konrad had several useful and thoughtful comments some of
which are given below. I am still thinking about them.

To a first approximation David is saying we need faster computers, while
Konrad is saying we need more experiments.

Even a small 100 residue protein (approx 1700 atoms) needs approximately
6000 waters (18000 atoms) to appropriately solvate (periodic box, with
minimal switched cutoffs so as to avoid protein-protein interactions) the
protein in an all atom Amber MD simulation for 100+ ps ...

The TIP3P water model was equilibrated at 300 K and 1 atm. In the
literature I see it used at temperatures below and above 300 K. In fact it
is used in non-isothermal simulations.
Is the TIP3P water model ok to use for (isothermal) MD at 400 K and 1 atm ?

Also various numbers are used as the minimum distance between solvent and
protein atoms (when adding water). I use 2.3 A.

With respect to Konrad's comments. I had thought the frictional
co-efficient was a constant in LD and it was chosen based on the
water-protein interface. In interesting that it is (possibly) the
intra-protein contacts that dominate. Although I would think this would
scale with the size of the protein and therefore the frictional
co-efficient would be protein dependent (or at least have two terms taking
into account the water-protein and protein-protein contacts and these in
turn would change during a simulation as the protein conformation changed
increasing or decreasing the solvent accessible protein surface).

I think the key point here ("For slow large-scale motions, you can leave
out electrostatics completely, assuming no unfolding of course ...") is
what is considered a structural change vs unfolding.

Thanks again for your thoughtful comments.


>On Mon, Jun 06, 2005, Laurence Lavelle wrote:
> > By protein motion I mean a folded protein in a constant temperature
> > simulation (for example with a distance dependent dielectric, no
> > electrostatic cutoffs, no periodic boundaries) and comparing the protein
> > dynamics at different temperatures.
>With the above conditions (no solvent, distance dependent dielectric) there is
>little reason to expect that either the average structure or the dynamics you
>see in the simulation will be realistic. If you want to get any reasonable
>account of protein dynamics, you need to be looking at MD simulations in
>explicit solvent. If you want good results as a function of temperature, you
>should take care that the water model you are using is known to produce good
>dynamical results vs. temperature for pure water.

>On 06.06.2005, at 23:43, Laurence Lavelle wrote:
>>In looking at the dynamical motion of a protein, is Amber (Cornell et
>>al. (1994) force field) (Amber 99 parameters) considered a reasonably
>>realistic protein force field (or, as good as or better than most) ?
>>In looking at the dynamical motion of a protein (for example using
>>Amber), what are the pros and cons to doing Molecular Dynamics vs
>>Langevin Dynamics vs Monte Carlo ?
>It all depends on what dynamical quantities you wish to calculate, and
>on which time scales.
>If you look at long time scales for a protein that has a single stable
>conformation, then you can get good results with very much simpler
>models at much lower cost. See
> K. Hinsen, A.J. Petrescu, S. Dellerue, M.C. Bellissent-Funel, G.R.
> Harmonicity in slow protein dynamics
> Chem. Phys. 261, 25-37 (2000)
>for an example. At the other end of the time scale spectrum, if your
>study involves quantum effects, no Molecular Mechanics model will be
>good enough.
>As for sampling techniques, note that Monte Carlo is not a dynamical
>technique at all (it has no time scale), even though in some situations
>a time scale can be assigned a posteriori. Langevin and Brownian
>dynamics add an implicit source of friction and thermal energy, which
>should correspond to some physical feature of the model, i.e. the
>explicit modelling should be less detailed.
>In this context, it is worth pointing that the major source of friction
>in a protein is not the solvent, as is frequently believed, but fast
>interactions in the protein itself. See the article quoted above for a
>>{Some will say it depends on the details (distance dependent
>>dielectric vs explicit solvent water molecules, no cutoffs vs with
>>switched or shifted cutoffs, with or without periodic boundary
>>conditions, etc.). However I am
>Again this depends on the time scales. For slow large-scale motions,
>you can leave out electrostatics completely, assuming no unfolding of
>course, because on such a coarse length scale the charge density is
>practically zero. On the other hand, for localized events, a correct
>representation of electrostatics is very important.
>> hoping (in addition to the above two questions) to get a general
>>sense of how realistic MD, LD and MC are with respect to illustrating
>>protein motion.
>We don't know that much about how realistic simulations of protein
>dynamics are. Experimental information is mostly on very small time
>scales or on time scales so long that they are out of reach of
>simulations. In between those two extremes, there is nothing that
>simulations could be tested against.
>Konrad Hinsen

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Received on Wed Jun 08 2005 - 07:53:01 PDT
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