AMBER Archive (2008)

Subject: AMBER: Fwd: Distorsion in protein and ligand during MD

From: Francesco Pietra (chiendarret_at_yahoo.com)
Date: Sun Jan 13 2008 - 03:57:43 CST

I badly forgot a piece of information about the analysis of trajectories at the
bottom of this letter. This info is added at the bottom, here it would be
cryptic.

--- Francesco Pietra <chiendarret_at_yahoo.com> wrote:

> Date: Sun, 13 Jan 2008 01:46:23 -0800 (PST)
> From: Francesco Pietra <chiendarret_at_yahoo.com>
> Subject: Distorsion in protein and ligand during MD
> To: Amber <amber_at_scripps.edu>
>
> With Amber 9, I am at a new protein-ligand system, coming from
> amber_score_everything structure (GB in DOCK6.1). Conditions successful from
> other cases are giving troubles here.
>
> I am looking for general advice - as far as it can be provided from my
> presentation - as I am in doubt whether to further carry out MD to hopefully
> bring the house in order, or select different conditions from the
> amber_score_everything stage on.
>
> The protein is ca 8000 atoms (ff ff99SB), the ligand ca 125 C H N O atoms (ff
> GAFF, param from Antechamber), the complex immersed in a POPC membrane
> solvated
> TIP3P (combining in leap), some steric clashes manually removed, minimization
> (no SHAKE) successful if carried out by steepest descent only, then
> conjugated
> gradient applied. Heating to 300K:
>
> &cntrl
> imin=0,irest=0, ntx=1,
> nstlim=25000, dt=0.002,
> cut=10,ntb=1,
> ntc=2,ntf=2,
> ntpr=500, ntwx=500,
> ntt=3, gamma_ln=2.0,
> tempi=0.0, temp0=300.0,
> ntr=1,
> restraintmask=":77-521 | :POP_at_O2, P1, O3, O4, O1, C15, C11, N, C12, C13,
> C14"
> restraint_wt=32,
> nmropt=1
> /
> &wt TYPE='TEMP0', istep1=0, istep2=25000,
> value1=0.1, value2=300.0, /
> &wt TYPE='END' /
>
> that is, with strong restraint on protein, ligand, and the polar head of
> POPC.
>
> Equilibration by twice applying:
>
> &cntrl
> imin=0, irest=1, ntx=5,
> nstlim=250000, dt=0.002,
> cut=10, ntb=2, ntp=1, taup=2.0,
> ntc=2, ntf=2,
> ntpr=1000, ntwx=1000,
> ntt=3, gamma_ln=2.0,
> temp0=300.0,
> ntr=1,
> restraintmask=":77-521 | :POP_at_O2, P1, O3, O4, O1, C15, C11, N, C12, C13,
> C14"
> restraint_wt=32,
> /
>
> also successful, judging from Amber Tutorial A3 scripts, i.e., constant
> density, temp, etot. Then, equilibration was continued for 500ps by removing
> restraints on POPC. From ptraj, measure rmsd showed a constant trend after
> 150ps.
>
> Production, by three times applying:
>
> &cntrl
> imin=0, irest=1, ntx=5,
> nstlim=250000, dt=0.0015,
> cut=10, ntb=2, ntp=1, taup=2.0,
> ntc=2, ntf=2,
> ntpr=1000, ntwx=1000,
> ntt=3, gamma_ln=2.0,
> temp0=300.0,
> /
>
> seems to be problematic, or I have a scarce understanding of what is going
> on,
> either the ligand is moving away from the pocket, or what else:
>
> I combined the three mdcrd with ptraj, either for the whole system, or by
> stripping POP WAT and box information.
>
> Let me tell about the latter. For reasons I don't understand, one molecule of
> water was not stripped from mdcrd, although it is called WAT. Therefore, I
> used
> that prmtop that was used for amber_score_everything, which provided the pdb
> file for the above-told work with Amber (docking was carried out with a
> molecule of crystallization water in the protein, so that this prmtop knows
> about WAT).
>
> RMSD Traj Tool in VMD about the loaded, combined and stripped mdcrd (add all,
> backbone) was run for:
>
> ---"top", i.e. comparing with respect to frame 0 out of 549 frames. The plot
> shows rmsd rising from ca 7, a small plateau at frames 100-110, a hill
> centered
> at ca frame 350, then a slow decreasing to ca 25 for the last (549) frame.
>
> --- "average", i.e., comparing to the average frame. The plot shows a steep
> decrease of rmsd from ca 22 to ca 17 at frame 250, then a steep rise to rmsd
> 22
> for to the last (549) frame.
>
> I don't tell about a similar analysis for the unabridged mdcrd as I think it
> is
> even less useful.

ADDED: Looking (VMD) at the last frame, The ligand appear to be highly
distorted, in particular the hydrogen atoms. Tetrahedral info has been lost.

Getting pdb from script

trajin production1-3.binpos
average production1-3_average.pdb pdb

(i.e., concerning the whole production reported above), this pdb shows the
ligand nearly OK. What I see (VMD) wrong there are the methyl groups only: the
C-H bonds are shorter and the hydrogens are closer to one another than for a
tetrahedral structure. All other C-H bond have normal length and orientation,
in particular the C N O backbone of the ligand is correct.

>
> I wonder whether from this description a suggestion may be offered where to
> put
> the hands.
>
> Thanks a lot
>
> francesco pietra
>
>
>
>
____________________________________________________________________________________
> Never miss a thing. Make Yahoo your home page.
> http://www.yahoo.com/r/hs
>

      ____________________________________________________________________________________
Never miss a thing. Make Yahoo your home page.
http://www.yahoo.com/r/hs
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