Since your simulations of the individual windows are about 50 ns, you
could first dismiss the first 10 ns for equilibration, and then perform
the WHAM analysis for 10-30 ns and 30-50 ns. If everything is fine, you
should see no drift.
If you want to have more data for the analysis you could also use 5ns ;
5-27.5ns and 27.5-50ns.
From the PMF it seems that the equilibrium state should be around 0.6
nm. To be sure, you can perform a normal simulation (without any
restraints) from you initial starting window (~0.4nm) and a window near
the minima (~0.6nm). Then after the equilibration phase, look at the
distribution of the distance along the reaction coordinate. If in both
cases the maximum is at ~0.6nm, this should be the 'true' equilibrium
state of the system (instead of the first window of the PMF calculation)
and i would measure \Delta G from this point.
Greetings
Thomas
Am 21.08.2012 17:25, schrieb gmx-users-requ...@gromacs.org:
On Tue, Aug 21, 2012 at 4:21 PM, Justin Lemkul <jalem...@vt.edu> wrote:
>
>
>On 8/21/12 11:18 AM, Steven Neumann wrote:
>>
>>On Tue, Aug 21, 2012 at 4:13 PM, Justin Lemkul<jalem...@vt.edu> wrote:
>>>
>>>
>>>
>>>On 8/21/12 11:09 AM, Steven Neumann wrote:
>>>>
>>>>
>>>>On Tue, Aug 21, 2012 at 3:48 PM, Justin Lemkul<jalem...@vt.edu> wrote:
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>On 8/21/12 10:42 AM, Steven Neumann wrote:
>>>>>>
>>>>>>
>>>>>>
>>>>>>Please see the example of the plot from US simulations and WHAM:
>>>>>>
>>>>>>http://speedy.sh/Ecr3A/PMF.JPG
>>>>>>
>>>>>>First grompp of frame 0 corresponds to 0.8 nm - this is what was shown
>>>>>>by grompp at the end.
>>>>>>
>>>>>>The mdp file:
>>>>>>
>>>>>>; Run parameters
>>>>>>define = -DPOSRES_T
>>>>>>integrator = md ; leap-frog integrator
>>>>>>nsteps = 25000000 ; 100ns
>>>>>>dt = 0.002 ; 2 fs
>>>>>>tinit = 0
>>>>>>nstcomm = 10
>>>>>>; Output control
>>>>>>nstxout = 0 ; save coordinates every 100 ps
>>>>>>nstvout = 0 ; save velocities every
>>>>>>nstxtcout = 50000 ; every 10 ps
>>>>>>nstenergy = 1000
>>>>>>; Bond parameters
>>>>>>continuation = no ; first dynamics run
>>>>>>constraint_algorithm = lincs ; holonomic constraints
>>>>>>constraints = all-bonds ; all bonds (even heavy atom-H bonds)
>>>>>>constrained
>>>>>>; Neighborsearching
>>>>>>ns_type = grid ; search neighboring grid cells
>>>>>>nstlist = 5 ; 10 fs
>>>>>>vdwtype = Switch
>>>>>>rvdw-switch = 1.0
>>>>>>rlist = 1.4 ; short-range neighborlist cutoff (in nm)
>>>>>>rcoulomb = 1.4 ; short-range electrostatic cutoff (in nm)
>>>>>>rvdw = 1.2 ; short-range van der Waals cutoff (in nm)
>>>>>>ewald_rtol = 1e-5 ; relative strenght of the Ewald-shifted
>>>>>>potential rcoulomb
>>>>>>; Electrostatics
>>>>>>coulombtype = PME ; Particle Mesh Ewald for long-range
>>>>>>electrostatics
>>>>>>pme_order = 4 ; cubic interpolation
>>>>>>fourierspacing = 0.12 ; grid spacing for FFT
>>>>>>fourier_nx = 0
>>>>>>fourier_ny = 0
>>>>>>fourier_nz = 0
>>>>>>optimize_fft = yes
>>>>>>; Temperature coupling is on
>>>>>>tcoupl = V-rescale ; modified Berendsen
>>>>>>thermostat
>>>>>>tc_grps = Protein LIG_Water_and_ions ; two coupling groups -
>>>>>>more
>>>>>>accurate
>>>>>>tau_t = 0.1 0.1 ; time constant, in ps
>>>>>>ref_t = 318 318 ; reference temperature,
>>>>>>one for each group, in K
>>>>>>; Pressure coupling is on
>>>>>>pcoupl = Parrinello-Rahman ; pressure coupling is on
>>>>>>for
>>>>>>NPT
>>>>>>pcoupltype = isotropic ; uniform scaling of box
>>>>>>vectors
>>>>>>tau_p = 2.0 ; time constant, in ps
>>>>>>ref_p = 1.0 ; reference pressure, in
>>>>>>bar
>>>>>>compressibility = 4.5e-5 ; isothermal
>>>>>>compressibility of water, bar^-1
>>>>>>; Periodic boundary conditions
>>>>>>pbc = xyz ; 3-D PBC
>>>>>>; Dispersion correction
>>>>>>DispCorr = EnerPres ; account for cut-off vdW scheme
>>>>>>; Velocity generation
>>>>>>gen_vel = yes ; assign velocities from Maxwell distribution
>>>>>>gen_temp = 318 ; temperature for Maxwell distribution
>>>>>>gen_seed = -1 ; generate a random seed
>>>>>>; These options remove COM motion of the system
>>>>>>; Pull code
>>>>>>pull = umbrella
>>>>>>pull_geometry = distance
>>>>>>pull_dim = N N Y
>>>>>>pull_start = yes
>>>>>>pull_ngroups = 1
>>>>>>pull_group0 = Protein
>>>>>>pull_group1 = LIG
>>>>>>pull_init1 = 0
>>>>>>pull_rate1 = 0.0
>>>>>>pull_k1 = 500 ; kJ mol^-1 nm^-2
>>>>>>pull_nstxout = 1000 ; every 2 ps
>>>>>>pull_nstfout = 1000 ; every 2 ps
>>>>>>
>>>>>>
>>>>>
>>>>>Based on these settings you're allowing grompp to set the reference
>>>>>distance
>>>>>to whatever it finds in the coordinate file. It seems clear to me that
>>>>>the
>>>>>sampling indicates what I said before - you have an energy minimum
>>>>>somewhere
>>>>>other than where you "started" with. What that state corresponds to
>>>>>relative to what you think is going on is for you to decide based on
>>>>>the
>>>>>nature of your system. Whatever is occurring at 0.6 nm of COM
>>>>>separation
>>>>>is
>>>>>of particular interest, since the energy minimum is so distinct.
>>>>>
>>>>
>>>>So based on this the deltaG will correspond to -5.22 as the initial
>>>>state was taken at 0.4 nm corresponding to 0 kcal/mol as the moment
>>>>corresponding to the minimum is the coordinate from SMD where last
>>>>hydrogen bond was broken. Would you agree?
>>>>
>>>
>>>Based on the very little information I have, no. It would appear that
>>>the
>>>0.4 nm separation is in fact some metastable state and the true energy
>>>minimum is at 0.6 nm of COM separation. What's going on at that
>>>location?
>>
>>
>>
>>My mistake. The initial grompp of 1st configuartion (where ligand
>>stakced on keratin surface) corresponds to 0.6 nm where
>>is the minimum. Thus deltaG would be -7.22 kcal/mol. Am I right? Or
>>Shall I take difference between 0 and 5.22 ?
>>
>>
>
>-7.22 kcal/mol sounds much more logical to me. If your first configuration
>is at the energy minimum, that's not something you ignore. The zero point
>can be set wherever you like with the g_wham flag -zprof0, so it's really
>rather arbitrary. The WHAM algorithm simply sets the leftmost window
>(smallest value along the reaction coordinate) to zero to construct the
>remainder of the PMF curve.
>
>
>>>
>>>
>>>>>I hope you're doing a thorough analysis of convergence if you're
>>>>>generating
>>>>>velocities at the outset of each run, and removing unequilibrated
>>>>>frames
>>>>>from your analysis.
>>>>
>>>>
>>>>
>>>>When I use WHAM I skip first 200 ps of each window as the equilibration.
>>>>
>>>
>>>That seems fairly short, especially given the generation of velocities in
>>>conjunction with the Parrinello-Rahman barostat, which can be very
>>>temperamental.
>>
>>
>>Would you suggest e.g. skip 1 ns?
>>
>
>I'm not going to make an arbitrary guess. It's up to you to analyze the
>timeframe required for whatever relevant observables to converge.
>
>
>-Justin
Thanks for this.
Steven
>
>--
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