RE: AMBER: Molecular dynamic

From: Ross Walker <>
Date: Thu, 8 Jul 2004 10:24:21 -0700

Dear Bo,

> I tried to run molecular dynamic with my protein structural
> model using Amber7.
> After the run, I notice that there are significant changes in
> the structure. All the helix regions became partial unfolded. A
> beta-sheet region connecting the N-terminal helix also turns to be
> unfolded. I checked the energy (total, potential and kinetic) levels,
> temperature, density & volume Vs. Time (ps) of the entire MD process
> (including equilibration and production stages). All remained
> in stable
> conditions after 20 ps run. And the mean pressure level is ~
> 1 atm after
> 50 ps. All these data indicated that I had a successful MD run.
> Furthermore, the RMSD level steady increased at first 20 ps, and was
> gradually increasing during the rest of the run.

It is not obvious what is happening here. It may actually be possible that
your system is actually more stable with those sections unfolded, although
if you started from a good crystal structure this is unlikely. You don't
mention specifically what you are simulating. Is it a protein made up of
standard amino acids? If not how did you get the parameters for the
non-standard parts, it could be these at fault. Also, you should check
things like di-sulphide bridges. These are not added by default and must be
manually specified. E.g Crambin will unfold if you don't add the disulphide
bridges when preparing the input files in leap.

It is also possible that your system is hydrogenated in an unfavourable way
leading to steric clashes that result in the system "almost" blowing up. You
could try running your minimisation in two stages where you initially
minimise just the waters and counter ions with weak (~10Kcal) restraints on
the protein and then do a second stage of minisation where you allow
everything to move.

Your methodology looks pretty good though. A couple of things I would
initially try is to:

1) check your system has the correct protonation. In particular check
histidine residues.

2) ensure your system was properly charge neutralised.

3) Try running the heating stage again but from 0K to 300K and set it to
write to your mdcrd file every step. Then you will be able to load the mdcrd
file into something like vmd and see what is initiating the unfolding. Does
it look valid or does it look like it is caused by steric issues from

> From related papers on line, most of them indicated that only minimal
> conformational change observed with their MD runs. I went
> back to check the template used for my structure modeling. The original
> structure template contains three MSE residues(?) in the
> helix regions.

Did you strip these for your MD??? Do you know what MSE residues are? A
picture would be good. I am guessing that you will need to include these and
will need to obtain parameters for them, either by analogy, finding
published parameters or by fitting.

> after MD run. The MSE in the original crystal structure may have some
> effects to stabilize the 3D-structure?

Most likely... Especially if you didn't include them in your MD run.
> Minimization solvates with cartesian restriantes for the solute
> &cntrl
> imin=1, ncyc=250, maxcyc=1000, ntpr=5,
> &end
> Group input for restrained atoms
> 100.0
> RES 1 220

Try weaker restraints here - say 10KCal.
> Initial molecular dynamic run 1: heating up the system, equilibration
> stage 1:
> &cntrl
> imin=0, irest=0, ntx=1,
> ntt=1, tempi=100.0, temp0=300.0, tautp=2, ig=209858,
> ntp=0,
> ntb=1, ntc=2, ntf=2,
> nstlim=5000, dt=0.002,
> ntwr=5000, ntwx=5000, ntpr=500,
> &end

Set ntwx and ntpr=1 so that you can get a detailed view of what is
> (from my last question posted about MD, I learned that the
> 'ntx' needs to
> be set at '7')

This is redundant in Amber 7 and Amber 8. NTX should normally be set to 5
for a restart. The box info will be read automatically if the run is a
periodic boundary run. NTX=7 is just included for backwards compatibility.

All the best

|\oss Walker

| Department of Molecular Biology TPC15 |
| The Scripps Research Institute |
| Tel:- +1 858 784 8889 | EMail:- |
| | PGP Key available on request |

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Received on Thu Jul 08 2004 - 18:53:00 PDT
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