Steered molecular dynamics on cyclic peptide nanotube ring separation

User discussions
1

GROMACS version: 2023
GROMACS modification: Yes/No
hello, I have applied a smd simulation between a cyclic peptide nanotube and a drug molecule. During 10 ns run, about 6th ns, the reference group that I pull the drug from it (ring one which name is cycle1 here) separates from the tube and the distance becomes more than its threshold and simulation is ceased. How can I stop this happening? I mean the separation? Can applying restraint on this ring help? Now It equals to 1000 for both backbone and sidechain restraints.

here is my pull.mdp file:
title = Umbrella pulling simulation
define = -DPOSRES
; Run parameters
integrator = md
dt = 0.002
tinit = 0
nsteps = 2500000 ; 500 ps
nstcomm = 10
; Output parameters
nstxout = 1000 ; every 10 ps
nstvout = 1000
nstfout = 500
nstxtcout = 500 ; every 1 ps
nstenergy = 500
; Bond parameters
constraint_algorithm = lincs
constraints = h-bonds
continuation = yes ; continuing from NPT
; Single-range cutoff scheme
cutoff-scheme = Verlet
nstlist = 5
ns_type = grid
rlist = 1.4
rcoulomb = 1.4
rvdw = 1.4
; PME electrostatics parameters
coulombtype = PME
fourierspacing = 0.12
fourier_nx = 0
fourier_ny = 0
fourier_nz = 0
pme_order = 4
ewald_rtol = 1e-5
optimize_fft = yes
; Berendsen temperature coupling is on in two groups
Tcoupl = v-rescale
tc_grps = Protein_drug lipid water_ions
tau_t = 1.0 1.0 1.0
ref_t = 300 300 300
; Pressure coupling is on
Pcoupl = c-rescale
pcoupltype = semiisotropic
tau_p = 1.0
compressibility = 4.5e-5 4.5e-5
ref_p = 1.0 1.0
refcoord_scaling = com
; Generate velocities is off
gen_vel = no
; Periodic boundary conditions are on in all directions
pbc = xyz
; Long-range dispersion correction
DispCorr = EnerPres
; Pull code
pull = yes
pull_ncoords = 1 ; only one reaction coordinate
pull_ngroups = 2 ; two groups defining one reaction coordinate
pull_group1_name = cycle1
pull_group2_name = drug
pull_coord1_type = umbrella ; harmonic potential
pull_coord1_geometry = direction ; simple distance increase
pull_coord1_vec = 0 0 -1
pull_coord1_groups = 1 2
pull_coord1_start = yes ; define initial COM distance > 0
pull_coord1_rate = 0.001 ; 0.01 nm per ps = 10 nm per ns
pull_coord1_k = 1000 ; kJ mol^-1 nm^-2

2

Use slower pulling rates, right now you’re at 1 nm/ns (or 1 m/s), which is quite extreme for any biologically relevant processes. If you pull delicate things too fast, they might fall apart.

You can choose to restrain the structure too, but then you will not get any structural response that might be relevant to the process of dissociation (if any - don’t know much about the host/ligand).

3

Thank you so much for your response.
How much puling force do you suggest?

4

It will depend on your resource availability and the particular setup, but now that multi-microsecond simulations are fairly common, I’d never try to pull anything out of a stable binding pose in less than 100-250 ns unless that’s for some sort of Jarzynski/Crooks free energy estimation.

5

Hi, What is the usual pulling rates in biological system?

6

simulate the cyclic peptide nanotube for long time scale- then use those structure for SMD. Your nanotube likely not stable.

7

I don’t know about nanotubes in biological systems ;) but there are relatively few instances in which things are actually pulled (like actin in muscles, or processive enzymes) - most biological interactions form and dissolve through thermal fluctuations, often accelerated by a chemical modification that makes the complex less stable.

For something like an RNA polymerase, the quite remarkable rate of 100 bases per second implies moving along the DNA by 30-40 nm. Myosin from some species can apparently move at up to 70 microns per second during the power stroke:
https://www.pnas.org/doi/full/10.1073/pnas.2120962119
which, again, would translate to 0.7 nm per 10 microseconds - to bring it to simulationally relevant scales. Nature wouldn’t be impressed by MD ;)

8

I have applied conventional md for 100 ns. Isn’t it enough?