Both could be problem.
RNA NMR structures can be quite bad, and then the simulation
does not have a chance to repair.
The starting structure may be not sufficiently correct
(I am however not telling this is the case, have no
experience with this particular system!!).
For comparison of X-ray vs. three contradicting (and mutually
contradicting) NMR structures see:
Conformations of flanking bases in HIV-1 RNA DIS kissing complexes studied by molecular dynamics
Reblova K, et al.
BIOPHYSICAL JOURNAL Volume: 93 Issue: 11 Pages: 3932-3949 2007
On the other hand, it is fair to admit that single stranded
hairpin loops capping
double-stranded stems represent
a very serious problem for force fields. In fact, published
papers basically do not show proper folding (despite claiming
to do so.) that would reproduce the native hairpin loop structures
as known from structural biology.
I am speaking about really single stranded terminal hairpin loops
at the end of stems,
not about paired internal loops.
We have commented on that
in few recent studies.
Molecular Dynamics and Quantum Mechanics of RNA: Conformational and Chemical Change We Can Believe In
Ditzler MA et al.
ACCOUNTS OF CHEMICAL RESEARCH Volume: 43 Issue: 1 Pages: 40-47 2010
Structural Dynamics of the Box C/D RNA Kink-Turn and Its Complex with Proteins: The Role of the A-Minor 0 Interaction, Long-Residency Water Bridges, and Structural Ion-Binding Sites Revealed by Molecular Simulations
Spackova N et al.
JOURNAL OF PHYSICAL CHEMISTRY B Volume: 114 Issue: 32 Pages: 10581-10593 2010
see specifically fig. 15 for hairpin loop degradation.
Single Stranded Loops of Quadruplex DNA As Key Benchmark for Testing Nucleic Acids Force Fields
Fadrna E, et al.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION Volume: 5 Pages: 2514-2530 2009
Normally, when starting structure is good, bsc0 provides quite
good behavior. In the above studies, we reported problems but
we were still able to get useful data (there are no perfect force fields).
You can send me pdb of your final structure
to sponer.ncbr.chemi.muni.cz and I can
have a look at it some time next week.
As for simulation set up, test some well behaving molecule, such as
Sarcin Ricin loop
Molecular Dynamics simulations of Sarcin Ricin rRNA motif. Nucleic Acids Research 34, 2006, 697-708
Here you have 1.0 A resolution X-ray benchmarks while we have
multiple very stable unpublished test 100+ ns trajectories (except of
occassional problems with the top hairpin, as noted above).
Another point, if you cut (not clear from your email) just
a short fragment from the whole motif, then the simulation
can easily by unstable.
best wishes, Jiri
-------------------------------------------------------
Jiri Sponer
Professor of Biochemistry
Head of Department of Structure and Dynamics of Nucleic Acids
Institute of Biophysics
Academy of Sciences of the Czech Republic
Kralovopolska 135
CZ-61265 Brno
Czech Republic
e-mail: sponer.ncbr.chemi.muni.cz
fax: 420 5412 12179
phone: 420 5415 17133
http://www.ibp.cz/labs/LSDNA/
-----------------------------------------------------------
> several ns to severely unwind. I have tried a variety of input
> parameters, but with little success. The latest input files are given
> below the message.
>
> The last force field I used was ff99bsc0 with counterions added and
> solvated with TIP3P water in a box with 14 A margins. I also tried
> restraining several bases at the cutoff point (where the rest of the
> full RNA would be), but with no positive effect on the conformation of
> the hairpin.
>
> Could you please take a look at the input files in case there is
> something's not right there?
> At this point, there are three possibilities:
> 1. Something is wrong with input, solvation, etc. (i.e. my fault)
> 2. The force field is inadequate for this problem
> 3. The published structure is physiologically irrelevant, and thus
> cannot be reproduced in a stable simulation.
>
>
> I would very much appreciate any advice.
>
> Thanks
>
> Sasha
>
>
>
> Minimization 1
> &cntrl
> imin = 1,
> maxcyc = 10000,
> ncyc = 5000,
> ntb = 1,
> ntr = 1,
> cut = 15
> /
> Hold the solute fixed
> 500.0
> RES 1 31
> END
> END
>
> Initial minimization whole system
> &cntrl
> imin = 1,
> maxcyc = 10000,
> ncyc = 5000,
> ntb = 1,
> ntr = 0,
> cut = 15
> /
>
> Heating
> &cntrl
> imin = 0,
> irest = 0,
> ntx = 1,
> ntb = 1,
> cut = 20,
> ntr = 1,
> ntc = 2,
> ntf = 2,
> tempi = 0.0,
> temp0 = 300.0,
> ntt = 3,
> gamma_ln = 2.0,
> nstlim = 25000, dt = 0.001,
> ntpr = 250, ntwx = 250, ntwr = 1000
> /
> Keep solute fixed with weak restraints
> 10.0
> RES 1 31
> END
> END
>
> Density equilibration
> &cntrl
> imin = 0,
> irest = 1,
> ntx = 5,
> ntb = 2,
> cut = 15,
> ntr = 1,
> ntp = 1,
> ntc = 2,
> ntf = 2,
> temp0 = 300.0,
> ntt = 3,
> gamma_ln = 2.0,
> nstlim = 25000, dt = 0.001,
> ntpr = 250, ntwx = 250, ntwr = 1000
> /
> Keep solute fixed with weak restraints
> 10.0
> RES 1 31
> END
> END
>
>
> First equilibration with some restraints on the solute
> &cntrl
> imin = 0,
> irest = 1,
> ntx = 5,
> ntb = 2,
> cut = 12,
> ntp = 1,
> ntc = 2,
> ntf = 2,
> ntr = 1,
> taup = 2.0,
> temp0 = 300.0,
> ntt = 3,
> tol = 0.000001,
> gamma_ln = 2.0,
> nstlim = 2000000, dt = 0.001,
> ntpr = 10000, ntwx = 10000
> /
> Set
> 10.0
> FIND
> * * B *
> SEARCH
> RES 1 31
> END
> END
>
>
> Full equilibration
> &cntrl
> imin = 0,
> irest = 1,
> ntx = 5,
> ntb = 2,
> cut = 12,
> ntp = 1,
> ntc = 2,
> ntf = 2,
> ntr = 0,
> taup = 2.0,
> temp0 = 300.0,
> ntt = 3,
> tol = 0.000001,
> gamma_ln = 2.0,
> nstlim = 2000000, dt = 0.001,
> ntpr = 10000, ntwx = 10000
> /
>
>
>
> Production simulation (500 ps run - one of many)
> &cntrl
> imin = 0, irest = 1, ntx = 7,
> ntb = 2, pres0 = 1.0, ntp = 1,
> taup = 2.0,
> cut = 10, ntr = 0,
> ntc = 2, ntf = 2,
> temp0 = 300.0,
> ntt = 3, gamma_ln = 2.0,
> nstlim = 250000, dt = 0.002,
> ntpr = 500, ntwx = 500, ntwr = 250000
> /
>
>
>
>
>
>
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Received on Fri Oct 15 2010 - 16:30:03 PDT
