How can one keep the reference group fixed in an SMD simulation?

User discussions
1

GROMACS version:2019.6
GROMACS modification: No
When performing SMD simulations to study ligand dissociation from a protein, I encounter a challenge due to the large size of my protein. It seems impractical to create a 400 Å box to encompass the entire protein as the reference group for SMD.
However, if I choose only a part of the protein as the reference group, this section of the protein moves in the opposite direction to the ligand during the SMD process, which is undesirable. In such cases, how do others usually address this issue? Thank you very much.
My .mdp file is based on the one automatically generated by CHARMM-GUI after constructing the membrane system.integrator = md
dt = 0.002
nsteps = 1000000
nstxout = 5000
nstvout = 5000
nstfout = 500
nstcalcenergy = 100
nstenergy = 500
nstlog = 500
;
cutoff-scheme = Verlet
nstlist = 20
rlist = 1.2
vdwtype = Cut-off
vdw-modifier = Force-switch
rvdw_switch = 1.0
rvdw = 1.2
coulombtype = PME
rcoulomb = 1.2
;
tcoupl = Nose-Hoover
tc_grps = SOLU MEMB SOLV
tau_t = 1.0 1.0 1.0
ref_t = 310 310 310
;
pcoupl = Parrinello-Rahman
pcoupltype = semiisotropic
tau_p = 5.0
compressibility = 4.5e-5 4.5e-5
ref_p = 1.0 1.0
;
constraints = h-bonds
constraint_algorithm = LINCS
continuation = yes
;
nstcomm = 100
comm_mode = linear
comm_grps = SOLU_MEMB SOLV
;smd set
pull = yes
pull-ngroups = 2
pull-group1-name = N
pull-group2-name = R162
pull-ncoords = 1
pull-coord1-type = umbrella
pull-coord1-geometry = direction
pull-coord1-groups = 1 2
pull-coord1-rate = 0.003
pull-coord1-dim = Y Y N
pull_coord1-k = 100
pull-coord1-vec = -18.4 17.0 0.0
pull_coord1_start = yes

Best regards.

2

So you’re pulling the ligand in the XY (membrane) plane, and the problem is, your transmembrane protein is large? I don’t really understand the issue of the relative movement; normally, you want to use either the binding interface or the COM of the binding domain as the reference group for SMD just to avoid distorting the geometry of the protein with pulling forces. Things can move relative to each other though and that’s fine.

If you only care about the protein-ligand interface, you can always extract your domain of interest only, and position-restraint its interface with the rest of the complex (far enough from the binding site), then proceed with your dissociation in a smaller system.

3

Thank you, milosz.wieczor, for your thoughtful response. I truly appreciate the insights you’ve provided, particularly regarding the use of the binding interface or the center of mass (COM) of the binding domain as the reference group to avoid distorting the protein structure. Your suggestion to extract the domain of interest and apply positional restraints is very helpful. Additionally, I am also exploring how the dissociation of small molecules impacts other parts of the protein, so your advice will be crucial in refining my approach. I plan to give the other parts of the protein some degree of freedom as well to better capture the dynamics. Thank you again!

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