[gmx-users] Steered MD simulation of drug molecules across the plasma membrane in gromacs 5.0.4

[mahender singh]

Hi
Christopher Neale and Justin

I used now following pull code (what i understood from the previous emails) to pull the drug across the membrane
; Pull code
pull        = umbrella
pull_geometry    = direction
pull_dim    = N N Y
pull_coord1_vec    =0 0 -1
pull_start    = yes 
pull_ngroups    =2
pull-ncoords    =1
pull_coord1_groups    = 1 2
pull_group1_name    = NPROT_ref
pull_group2_name    = LIG 
pull_coord1_rate    = -0.002        ; 0.002 nm per ps = 2 nm per ns
pull_coord1_k        = 1000        ; kJ mol^-1 nm^-2
pull_nstxout    = 50        ; every 1 ps
pull_nstfout    = 50        ; every 1 ps

there was no error and the molecule was able to cross the membrane from one side to the other side in a single SMD.
But my concern here is the pullf.xvg output, because in the graph all the force is in negative sign. but if I consider the magnitude of the force, it's giving me the expected graph as there will be increase in the force when drug will enter in the membrane. Can you kindly comment of the statement. 

with regards
Mahender Singh


> Thank you dear Justin and Christopher Neale for your help.
> 
>  Solute is at -z relative to the bilayer and wants to pull toward +z from the bulk water on the -Z to the +z bulk water through the membrane.
> I observed that the + and the - sign in the pull_coord1_rate is associated with increase or decrease in the COM distance between the pull group and the reference group, respectively. 
> I am trying to split simulation into two parts i.e. each leaflet as separate SMD simulation. 
> When solute is moving from the -z to the center of the bilayer, it will stop here as pull_coord1_rate = -0.0020 (decrease in the COM, pull force will be - in sign, am I right that sign in force values is negative because decrease in the distance between COM of two group with time is happening), still in the last frame, COM of the molecule will not moves to the +z side and I am not able to do the second part of the simulation by setting pull_start=yes , as if I will change the pull_coord1_rate = 0.0020 it will pull it back in the -z direction (pull force will be in positive sign) (pull_geometry= distance).
> 
> @Christopher Neale
> I will try the following setting and will let you know the results.
> 
> @ Justin
> When I am pulling the molecule from the center of bilayer to the bulk water and the same molecule from the bulk water to the center of bilayer (by changing the sign in the pull_coord1_rate = -/+0.0020 ). pull-force v/s time graphs are looking like following (first graph is the pulling of molecule from water to the center of bilayer and second graph is from the center of bilayer to the bulk water). My query was the - and the + sign of the pull force, which I think is due to the increase and decrease in the COM distance between the pull group and the reference group, am I right?
>               
>               
> 
> with regards
> Mahender singh
> 
> 
> > Dear Justin:
> > 
> > I think you are correct. It may not even really be that much of a hassle though one may need to be very careful in system setup for umbrellas near the center of the bilayer when using pull_start=yes rather than pull_coord1_init (i.e., one may need to make sure that the solute COM is on the side of the bilayer that one specifies with pull_coord1_vec, though having not used it myself perhaps this is not even an issue?). Separately, I presume that pull_coord1_init=0 should be identical with pull_coord1_vec = 0 0 1 or pull_coord1_vec = 0 0 -1, though if I was using the new code that would be something I would check at the outset.
> > 
> > Dear Mahender:
> > 
> > Based on Justin's suggestion and your initial mdp file, you should try something like the following. I'm still using gromacs 4.6.7 so I can not verify the accuracy of your other parameters (or even be entirely sure about these ones, but they are worth a try).
> > 
> > ;; Presuming that you start with the solute at +z relative to the bilayer and want to pull toward -z
> > pull        = umbrella
> > pull_geometry    = direction
> > pull_dim    = N N Y
> > pull_coord1_vec = 0 0 1
> > pull_coord1_rate = -0.002
> > pull_start = yes
> > 
> > ;; I presume that 
> > ;; pull_coord1_vec = 0 0 1 and pull_coord1_rate = -0.002 
> > ;; is identical to
> > ;; pull_coord1_vec = 0 0 -1 and pull_coord1_rate = 0.002 
> > 
> > ;; I am not sure if pull_dim = N N Y is necessary, but I don't see how it could hurt.
> > ;; Presumably the distance and the vector on which the pull_coord1_rate acts are already going to be entirely along z due to pull_coord1_vec , but I'd test that too if not using pull_dim = N N Y 
> > 
> > Please report back whether this works or whether you get strange behaviour when you hit the bilayer center.
> > 
> > ________________________________________
> > From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Justin Lemkul <jalemkul at vt.edu>
> > Sent: 22 April 2015 08:12
> > To: gmx-users at gromacs.org
> > Subject: Re: [gmx-users] Steered MD simulation of drug molecules across the plasma membrane in gromacs 5.0.4
> > 
> > On 4/21/15 6:54 AM, Christopher Neale wrote:
> > > Dear Mahender:
> > >
> > > It's a real pity that the pull_geometry = position has been removed. So now it's impossible to do umbrella sampling of a solute across a lipid bilayer properly? Anyway, I see a note about this removal here ( http://redmine.gromacs.org/issues/1346 ), though no reason is given. I'd suggest that you revert to a more functional version of gromacs ;)
> > >
> > > Hopefully I'm missing something and somebody else can point you to a better solution.
> > >
> > 
> > I think the behavior can be recovered with "direction" geometry, but that
> > requires each half of the symmetric sampling windows to be set up separately, I
> > think, rather than just a continuous vector like "position" used to provide.
> > That's a shame if true.  It's a workaround, but it's much less convenient.
> > 
> > -Justin
> > 
> > --
> > ==================================================
> > 
> > Justin A. Lemkul, Ph.D.
> > Ruth L. Kirschstein NRSA Postdoctoral Fellow
> > 
> > Department of Pharmaceutical Sciences
> > School of Pharmacy
> > Health Sciences Facility II, Room 629
> > University of Maryland, Baltimore
> > 20 Penn St.
> > Baltimore, MD 21201
> > 
> > jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> > http://mackerell.umaryland.edu/~jalemkul
> > 
> > ==================================================
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