Subject: Protein dynamics.

From: Laurence Lavelle <lavelle.-at-.mbi.ucla.edu>
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.

Laurence

>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.
>
>...dac

>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.
>Kneller
>   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
>demonstration.
>
>>{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