[gmx-users] Umbrella Sampling - Ligand Protein

[Steven Neumann]

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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