[gmx-users] Umbrella Sampling - Ligand Protein

Steven Neumann s.neumann08 at gmail.com
Sun Mar 11 17:50:00 CET 2012 

Hi Justin,

As you advised I reduced number of my windows and I obtined histogram:

http://speedy.sh/2b9dT/histo.JPG

Which looks really good.
The corresponding profile:

http://speedy.sh/y8Ssz/profile.JPG

I do not understand it. Does my deltaG of binding correspond to everything
above 0 kcal/mol which is 6 kcal/mol?

Thank you in advance,

Steven

On Thu, Mar 8, 2012 at 2:42 PM, Steven Neumann <s.neumann08 at gmail.com>wrote:

>
>
>  On Thu, Mar 8, 2012 at 2:18 PM, Justin A. Lemkul <jalemkul at vt.edu> wrote:
>
>>
>>
>> Steven Neumann wrote:
>>
>>> Dear Gmx Users, Dear Justin,
>>>  I pulled my ligand away from my protein. Ligand was attached to lower
>>> part of my protein, I pulled in Z coordinate it using:
>>>
>>> ; Run parameters
>>>
>>> integrator = md ; leap-frog integrator
>>>
>>> nsteps = 5000000 ; 2 * 5000000 = 10 ns
>>>
>>> dt = 0.002 ; 2 fs
>>>
>>> tinit = 0
>>>
>>> nstcomm = 10
>>>
>>> ; Output control
>>>
>>> nstxout = 50000 ; save coordinates every 100 ps
>>>
>>> nstvout = 50000 ; save velocities every
>>>
>>> nstfout = 5000
>>>
>>> nstxtcout = 5000 ; every 10 ps
>>>
>>> nstenergy = 5000
>>>
>>> ; Bond parameters
>>>
>>> continuation = yes ; 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
>>>
>>> rlist = 0.9 ; short-range neighborlist cutoff (in nm)
>>>
>>> rcoulomb = 0.9 ; short-range electrostatic cutoff (in nm)
>>>
>>> rvdw = 0.9 ; 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 = 298 298 ; 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 = 1.0 ; 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 = no ; assign velocities from Maxwell distribution
>>>
>>> ; 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 = LIG182
>>>
>>> pull_init1 = 0
>>>
>>> pull_rate1 = 0.0
>>>
>>> pull_k1 = 200 ; kJ mol^-1 nm^-2
>>>
>>> pull_nstxout = 1000 ; every 2 ps
>>>
>>> pull_nstfout = 1000 ; every 2 ps
>>>
>>> Following Justin's tutorial I used perl script to extract coordinate for
>>> each window.
>>>
>>> 0       2.4595039
>>>
>>> 1       2.4745028
>>>
>>> ...
>>>
>>> 500    8.74
>>>
>>> My ligand at the begining was at such distance as it was in the lower
>>> part of the protein. Then I used 0.1 nm spacing at the begining (till 4 nm)
>>> and 0.2 nm later on.
>>>
>>> And following equilibration in each window I run umbrella sampling for
>>> 10ns in app 49 windows:
>>>
>>> Run parameters
>>>
>>> integrator = md ; leap-frog integrator
>>>
>>> nsteps = 5000000 ; 2 * 5000000 = 10 ns
>>>
>>> dt = 0.002 ; 2 fs
>>>
>>> tinit = 0
>>>
>>> nstcomm = 10
>>>
>>> ; Output control
>>>
>>> nstxout = 50000 ; save coordinates every 100 ps
>>>
>>> nstvout = 50000 ; save velocities every
>>>
>>> nstfout = 5000
>>>
>>> nstxtcout = 5000 ; every 10 ps
>>>
>>> nstenergy = 5000
>>>
>>> ; Bond parameters
>>>
>>> continuation = yes ; 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
>>>
>>> rlist = 0.9 ; short-range neighborlist cutoff (in nm)
>>>
>>> rcoulomb = 0.9 ; short-range electrostatic cutoff (in nm)
>>>
>>> rvdw = 0.9 ; 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 = 298 298 ; 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 = 1.0 ; 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 = no ; assign velocities from Maxwell distribution
>>>
>>> ; 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 = LIG182
>>>
>>> pull_init1 = 0
>>>
>>> pull_rate1 = 0.0
>>>
>>> pull_k1 = 200 ; kJ mol^-1 nm^-2
>>>
>>> pull_nstxout = 1000 ; every 2 ps
>>>
>>> pull_nstfout = 1000 ; every 2 ps
>>>
>>>
>>> My PMF profile:
>>>
>>> http://speedy.sh/zerqZ/**profile.JPG<http://speedy.sh/zerqZ/profile.JPG>
>>>
>>> My histogram: http://speedy.sh/PyhnN/Histo.**JPG<http://speedy.sh/PyhnN/Histo.JPG>
>>>
>>> Why g_wham takes into account distances below 2.45 nm as the 1st
>>> structure was at 2.45. If I get rid of the distances below 2.45 (those
>>> weird values PMF values) I obtain beautiful profile:
>>>
>>> http://speedy.sh/TUXGC/**profile1.JPG<http://speedy.sh/TUXGC/profile1.JPG>
>>>
>>> Please, explain!
>>>
>>>
>> The way you're thinking about distance is not consistent.  Again, this is
>> a hazard of trying to map my tutorial onto your problem.  You say you have
>> a ligand bound to the "lower part" of your protein, and then you're pulling
>> in the z-direction.  The COM distance (as measured by g_dist and extracted
>> using my script) is not equivalent to the distance along the reaction
>> coordinate, if that reaction coordinate is only one dimension.  In the
>> tutorial, it was.  Here, it is not, hence the massive sampling defects that
>> you're observing and considerable redundancy in many of your windows.
>>
>> Check the output of grompp for the actual restraint distances that mdrun
>> will interpret.  They are printed to the screen.
>>
>> -Justin
>>
>
> Thank you Justin!!!
>
> Steven
>
>
>
>
>>
>> --
>> ==============================**==========
>>
>> Justin A. Lemkul
>> Ph.D. Candidate
>> ICTAS Doctoral Scholar
>> MILES-IGERT Trainee
>> Department of Biochemistry
>> Virginia Tech
>> Blacksburg, VA
>> jalemkul[at]vt.edu | (540) 231-9080
>> http://www.bevanlab.biochem.**vt.edu/Pages/Personal/justin<http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin>
>>
>> ==============================**==========
>> --
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>>
>
>
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