Dear Prokopios,
Thank you for your questions! I looked at your setups, and as a follow-up to Taisung's message, I have some questions for clarification -
1) The tiMerge command had the third ligand :3378 included in the <mol2mask>, is there any particular reason you want to do so? It seemed to me that you intended to do tiMerge :1-3378 :3379-6756 :362 :3740
2) In the trajectories at the TI stage, are there any close contact or overlap between atoms, especially before the simulations crashed due to the box dimension changes? Did the density change immediately after the simulation started?
If the setup is correct, one possible solution is to try running the simulations using the CPU code to see if it still has the same error. Alternatively, you could run short NPT on GPU for 5 ps and then restart it for another 5 ps, and then restart it a third time for N-10 ps where N is the number of ps you originally wanted to run NPT for.
You may want to take a look at the tutorial for running TI with AlChemical Enhanced Sampling (ACES) method
https://ambermd.org/tutorials/advanced/tutorial39/index.php and these papers
https://doi.org/10.1021/acs.jctc.2c00697 ,
https://doi.org/10.1021/acs.jcim.2c00879 where you could simulate the mutation of one particular residue on the protein.
Regards,
Shi
________________________________
From: accuratefreeenergy.gmail.com <accuratefreeenergy.gmail.com>
Sent: Monday, July 24, 2023 6:22 PM
To: Shi Zhang <sz550.chem.rutgers.edu>
Subject: FW: [AMBER] Thermodynamic Integration problems
-----Original Message-----
From: accuratefreeenergy.gmail.com <accuratefreeenergy.gmail.com>
Sent: Monday, July 24, 2023 2:52 PM
To: 'AMBER Mailing List' <amber.ambermd.org>; 'Prokopios Andrikopoulos' <prokopios.andrikopoulos.lf1.cuni.cz>
Subject: RE: [AMBER] Thermodynamic Integration problems
Hi Prokopios,
Based on the reported large difference between the MD and TI energies, your input topology and/or coordinate files might be problematic. I can take a quick look if you don't mind giving me your input files.
Best,
Taisung
On Mon, Jul 24, 2023 at 12:27 PM Prokopios Andrikopoulos via AMBER < amber.ambermd.org> wrote:
> Dear AMBER Users,
> I've been trying to do a TI for a mutation (res position 362) on a
> quite large trimer (1125 res per chain with a ligand at each chain at
> positions
> 3376-3378 - the ligand associated to the mutation is at 3378). I'm
> using ff14sb with TIP3P via the Amber 22 pmemd.cuda and the parmed
> from Amber 18
> (v22 parmed does not work on my cluster installation atm). I've
> adapted the relaxation regime from tutorial 3.1, by changing ntmin=2,
> ntf=1 and ntp=1 to make it acceptable for TI. I do a minimization >
> slow heating > and a series of 1ns constant pressure runs (with one
> more minimization
> in-between) releasing slowly the restrains as in tutorial 3.1. The
> relaxation regime works without any problems without the TI keywords
> (icfe, clambda etc.) on the normal prmtop using either a box or
> truncated octahedron for solvation. When I prepare the dual topology
> parm+rst7 is where the problems start. My parmed command is: tiMerge
> :1-3377 :3378-6754
> :362 :3739. Parmed moves the mutated res in the merged files right
> after the 1st chain, so in the relaxation inputs I have to point to
> 1126 instead, with the associated ligand at 3379.
>
> While the normal relaxation w/out TI reports a normal Density of
> ~1.00, the TI calculations density is reported in the 0.12-0.25 range
> in the constant pressure runs. A difference in energy is also evident
> in the initial minimization between the normal system and the TI
> complex with λ =
> 0.0: i.e. after 1000 min steps, this is EAMBER = -2180402.3012 and
> -2171818.4624 for the normal and TI calculation, respectively.
> Below are inputs for the complex with λ = 0.0. The input for the
> constant pressure run is the 4th in the regime with reduced backbone
> restrains. This fails for all λ values at 65-%75% of the total steps with the ERROR:
> Calculation halted. Periodic box dimensions have changed too much
> from their initial values. I would appreciate any help with this
> problem, and I can provide more details for the calculations.
>
> A secondary problem I have encountered is when I use a truncated
> octahedron for the solvation of the system with solvateOct. I use this
> command in leap for the complex and the protein: setBox
> protein/complex vdw { x = y = z }, and then I manually edit the last
> line of
> protein/complex.rst7 and merged_protein/complex.rst7 with the angles a
> = b = c = 109.47. When I run the calculation, it halts with Error:
> ifbox=2 in prmtop but angles are not correct. Incidentally, when I set
> ifbox=3 it runs without this error. Is this an acceptable solution?
>
> minimisation
> &cntrl
> imin = 1, ntmin = 2, maxcyc = 10000,
> ntpr = 50, ntwe = 0, ntwr = 500,
> ntb = 1, ntp = 0, ntf = 1, ntc = 2,
> ntx = 1, ntr = 1, ioutfm = 1, ntxo = 2,
> cut = 10.0,
> restraintmask = ':1-3379',
> restraint_wt = 100.,
>
>
> icfe = 1, ifsc = 1, clambda = 0.0, scalpha = 0.5, scbeta = 12.0,
> logdvdl = 0,
> timask1 = ':362', timask2 = ':1126',
> scmask1 = ':362', scmask2 = ':1126', /
>
> &ewald
> /
>
>
> heating to 298K
> &cntrl
> imin = 0, nstlim = 1000000, irest = 0, ntx = 1, dt = 0.001,
> ntt = 3, temp0 = 298.0, tempi = 100.0, tautp = 1.0, ig = -1,
> ntc = 2, ntf = 1,
> ntb = 1, ntp = 0, tol = 0.00001,
> ioutfm = 1, iwrap = 0, ntxo = 2, nscm = 0, cut = 8.0,
> ntwe = 0, ntwx = 10000, ntpr = 1000, ntwr = 1000,
>
> nmropt = 1, gamma_ln = 1.,
> ntr = 1, restraint_wt = 100.,
> restraintmask=':1-3379',
>
> icfe = 1, ifsc = 1, clambda = 0.0, scalpha = 0.5, scbeta = 12.0,
> logdvdl = 0,
> timask1 = ':362', timask2 = ':1126',
> scmask1 = ':362', scmask2 = ':1126', /
>
> &ewald
> /
>
> &wt
> type='TEMP0',
> istep1 = 0, istep2 = 1000000,
> value1 = 100., value2 = 298.
> /
>
> &wt type = 'END'
> /
>
> 4th constant pressure run of 1ns
> &cntrl
> imin = 0, nstlim = 1000000, dt = 0.001,
> irest = 1, ntx = 5, ig = -1,
> temp0 = 298.0,
> ntc = 2, ntf = 1,
> ntwx = 10000, ntwe = 0, ntwr = 1000, ntpr = 1000,
> cut = 8.0, iwrap = 0,
> ntt = 3, gamma_ln = 1.0, ntb = 2, ntp = 1, barostat = 2,
> nscm = 0,
> ntr = 1, restraintmask = "@CA,N,C", restraint_wt = 1.
> ioutfm = 1, ntxo = 2,
>
> icfe = 1, ifsc = 1, clambda = 0.0, scalpha = 0.5, scbeta = 12.0,
> logdvdl = 0,
> timask1 = ':362', timask2 = ':1126',
> scmask1 = ':362', scmask2 = ':1126', /
>
> &ewald
> /
>
>
> Thanks for any suggestions
> P. A.
>
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