Hi Rory,
That the Na+ ions associate with the phosphate oxygens sounds like
something that *should* happen during the simulation, since it is something
that does happen in situ.
Na+ should interact with phosphate groups either diffusely (through the
first hydration shell) or by chelating an oxygen atom.
However, the experimental data for ion-water exchange rate says (and ion
parameters match!) that these events are fast, happening on the 10^-10 s
timescale (sub-nanosecond, maybe tens to hundreds of picoseconds
https://pubs.acs.org/doi/10.1021/ct3000734).
I think you're going to introduce more problems by creating restraints than
by allowing the Na+ to equilibrate, even if part of the time it's
associating with the phosphates.
Otherwise, I'd jump into using a GB model where you don't have to "worry"
about quantifying these explicit interactions.
-Christina
On Tue, Apr 25, 2023 at 6:18 AM Rory Crean via AMBER <amber.ambermd.org>
wrote:
> Hello,
>
>
> I have a standard periodic box protein ligand system containing 9 Na+
> counterions for neutralisation purposes.
>
> The ligand contains 2 phosphate groups which interact with the protein and
> throughout MD simulations several Na+ ions can come and stick to these
> phosphate groups which is not ideal/wanted.
>
>
> I've therefore been working on trying to place harmonic restraints to
> prevent the sodium ions from coming too close to the phosphate groups.
>
> I've tried a few different schemes, in each case, each ion has its own
> restraint and it is to a group of backbone atoms whose combined center of
> mass is close to both phosphate groups. I've also tried more direct
> restraints between the phosphate groups and each ion (I wanted to avoid
> restraints on the phosphate groups to avoid disturbing it, but that's off
> the topic for this email).
>
>
> I see in the log files the restraints are read in and the restraints
> themselves are working/doing what is expected most of the time. The issue
> is after some time (in the 10s of ns), I can observe a sodium ion
> interacting with a phosphate group after post-processing the trajectory.
> When I look at the DISANG file (containing the calculated restraint
> distances, the distances are always above the thresholds). Sometimes,
> shortly after this the simulation crashes (presumably due to the high
> forces generated by the restraints after the system images the ion,
> resulting in the ion being very close to the ligand).
>
>
> My thinking/understanding is this is an imaging/periodicity issue in which
> the restraint distances are not correctly imaged at every frame meaning the
> ion can in some cases come very close to the ligand without the restraint
> activating. Does that sound right?
>
>
> Looking through the forum I seen suggestions like setting "nscm" to be
> greater than the timestep. I tried that but it unfortunately did not work
> for me. I've also played with "iwrap".
>
>
> I also tried to use plumed to define the restraints but ultimately had the
> same issue.
>
>
> Does anyone have any suggestions on what could be done/tried? My only
> thought at the moment is to just remove the counter ions and use the
> neutralising plasma approach.
>
>
> Thanks for reading my question.
>
> Kind regards,
>
> Rory
>
>
> Below is an example production md input file and restraint file, happy to
> provide more inputs/info if useful of course
>
> ############# production file ###########
>
> 400 ns NPT MD production
> &cntrl
> imin=0, irest=1, ntx=5, iwrap=0,
> nstlim=200000000, dt=0.002,
> ntpr=5000, ntwx=5000, ioutfm=1, ntwr=50000,
> ntc=2, ntf=2, cut=8.0,
> ntb=2, ntp=1, pres0=1.0, taup=1.0,
> ntt=3, tempi=298.0, temp0=298.0, gamma_ln=5.0, ig=-1,
> nmropt=1, nscm=200000001,
> /
> &wt type='DUMPFREQ', istep1=5000,
> /
> &wt type='END'
> /
> DISANG=distrestraint.RST
> DUMPAVE=dist_vs_t.txt
>
> ############# restraint file ###########
> &rst
> r1=18,r2=20,r3=45,r4=47,
> rk2=10.0,rk3=0.0,
> iresid=0,
> iat=-1,4003
>
> igr1=173,175,183,184,756,758,774,775,2002,2004,2010,2011,2012,2014,2032,2033,2650,2652,2662,2663
> /
> &rst
> r1=18,r2=20,r3=45,r4=47,
> rk2=10.0,rk3=0.0,
> iresid=0,
> iat=-1,4004
>
> igr1=173,175,183,184,756,758,774,775,2002,2004,2010,2011,2012,2014,2032,2033,2650,2652,2662,2663
> /
> ....
> [repeated for each ion numbered between 4003 and 4014]
> ...
> &rst
> r1=18,r2=20,r3=45,r4=47,
> rk2=10.0,rk3=0.0,
> iresid=0,
> iat=-1,4014
>
> igr1=173,175,183,184,756,758,774,775,2002,2004,2010,2011,2012,2014,2032,2033,2650,2652,2662,2663
> /
>
>
> --
> Rory Crean
>
>
>
>
>
>
>
>
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--
-----------------------------------------------------------------
Christina Bergonzo
Research Chemist
Biomolecular Measurement Division, MML, NIST
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Received on Tue Apr 25 2023 - 08:30:03 PDT
