Re: [AMBER] Reg: Query on distance restrain and its effect on conformation

From: GG Smith <>
Date: Thu, 12 Mar 2015 01:20:30 -0400

Dear Jason,

Thank you very much for your suggestions/useful comments. Will try it
out & let know.


On 11/03/2015, Jason Swails <> wrote:
> On Wed, 2015-03-11 at 00:41 -0400, GG Smith wrote:
>> Dear Amber Users,
>> Am a graduate student venturing recently in to dynamics, I
>> would like to humbly seek your advice and suggestion regarding a
>> simulation attempted by me on Protein+nucleic acid complex .
>> I had written to amber forum about the ideal range force constant to
>> be used for restraining distance b/w specific residues of protein &
>> nucleic acid backbone. I was suggested to use ~ 20 kcal/mol. Am using
>> AMBER12 (ff12SB) program.
>> Pls. find below the steps i followed:
>> *Am trying to position a nucleic acid duplex with enzyme by imposing
>> (Guiding) a specific distance between them (between side chain of
>> certain amino acid and phosphate backbone atom.
>> *The starting distance between them was ~ 7 Angstrom and i wanted it
>> in range of ~5.0 A.
>> This is my restraint file;
>> # 16 ASP OD2 42 DNA O1P
>> &rst
>> ixpk= 0, nxpk= 0, iat= 292, 1317, r1= 4.30, r2= 4.80, r3= 4.90, r4= 5.40
>> rk2=20.0, rk3=20.0, ir6=1, ialtd=0,
>> &end
>> *During equilibration process of free energy minimization, i imposed
>> this condition. I was able to achieve it to near value by setting rk2
>> & rk3 to 20 kcal/mol. I continued it in pre-equil production run and
>> then for 5ns of production run. But during last 1 ns i see that some
>> Watson & crick paired bases are not maintaining planarity & at times
>> losing hydrogen bond and duplex structure distorted a bit. I have a
>> doubt that whether this is due to continued restraint during
>> production run MD too.
>> I have done MD simulation for the same system without restraint and
>> the duplex looks fine and the hydrogen bonds between WC paired
>> bases are maintained.
> This suggests to me that the problem could be with the restraint. 20
> kcal/mol is a fairly strong restraint (although weaker than most bonds).
> At a distance of 2 Angstroms from equilibrium distance, this introduces
> a 80 kcal/mol/A force on each of the two atoms (in different
> directions). To see how this compares to "typical" forces, attached is
> a histogram of the magnitudes of the forces on every atom in a
> particular (well-equilibrated) snapshot from one of my own simulations.
> As you can see, there are *some* forces larger than 80 kcal/mol/A, but
> very few. In fact, in this 20K atom system (using explicit solvent with
> PME), only 38 atoms had forces this large (about 0.2% of all atoms in
> the system). And I suspect this is a sustained force (i.e., it remains
> a large force for several steps).
> Think about what this restraint is doing -- you are attaching a spring
> between two individual atoms so that the entire force of the restraint
> is applied to those two atoms. Try and picture how pulling a floppy
> tube-like structure through water by pulling hard on a single point
> could distort the structure of that molecule.
> It is fairly easy to rationalize why the force could be the cause of the
> structure distorting (it doesn't mean that this is definitely the
> culprit, but it seems to me to be a sensible hypothesis). So I would
> suggest looking for a way to be gentler about moving the NA duplex where
> you want it. Some ideas:
> - Try pulling in steps. You can use Steered MD to move the target
> distance during the course of the simulation (see jar=1 in the reference
> manual). Or you can run this stage in multiple steps, each one setting
> the distance closer to where you want it.
> - Try using center of mass restraints or multiple distance restraints in
> order to distribute the force more evenly over the duplex.
> This might take some playing around to get things positioned the way you
> want them. Of course, there's always the possibility that this is
> simply what happens when the NA and protein come this close in those
> starting configurations. In that case, you'll need a different approach
> altogether.
> HTH,
> Jason
> --
> Jason M. Swails
> BioMaPS,
> Rutgers University
> Postdoctoral Researcher

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Received on Wed Mar 11 2015 - 22:30:03 PDT
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