Re: [AMBER] Question of targeted molecular dynamics simulation

From: Dr. Anselm Horn <>
Date: Fri, 15 Jan 2021 18:14:18 +0100

Dear 吴晓东.

although I'm no expert on TMD, a short comment on your setup:
Starting from the ligand-free structure and pulling the ligand back into
the binding pocket might not be as easy as it might seem at the first
glance; although the target structure is known, the ligand needs to
follow a certain path to fit into the binding pocket. Plain back-pulling
(i.e. a decrease of the distance to the targe structure) might not be
working, if the ligand is not restrained e.g. in translation and thus
can explore its full conformational freedom.

Maybe you can go the other way and pull the ligand out of the binding
pocket, that depends on your type of investigation.
You could also setup a large number of simulations and hope that some of
them will find the reference structure...

(In our group, we once were lucky to observe a spontaneous binding event
of a small ligand to a GPCR, by chance.
DOI: 10.1007/s00894-018-3873-7)



On 01/15/2021 03:37 AM, 吴晓东 wrote:
> Dear all,
> I have problems with targeted MD.
> I run targeted MD by using Amber18. I have performed 10-ns TMD. In my simulated system, there is a small molecule drug located at 24Å from the protein binding pocket (the crystal structure is a complex, and I pulled the ligand out of the pocket). As shown in the run command, I gave a reference structure (crystal sturucture postion) for this simulation. However, the TMD can't force the drug moving back to the protein binding pocket with rmsd =0. After the 10-ns TMD simulation, the trajectory show that the drug located at 14Å around the portein binding pocket.
> For this problem, I want to know if there is something wrong with my input file syntax, or if my simulation time is not long enough? The input file (sander.in5) is shown below.
> Run command:
> mpirun -bind-to core -np 24 sander.MPI -O -i sander.in5 -o sander.out5 -p prmtop -c mdrest4 -r mdrest5 -x mdcrd5 -ref TMDcrd
> Input file (sander.in5) :
> Production 10 ns
> &cntrl
> imin=0,irest=0,
> nstlim=5000000,dt=0.002,
> temp0=300.0,ntt=3,gamma_ln=2.0,
> ntc=2,ntf=2,ntx=1,nscm=0,tol=0.00001
> cut=8.0,
> ntpr=500,ntwx=2000,ntwv=0,ntwe=0,ntxo=1,iwrap=1,
> ntb=2,ntp=1,pres0=1.0,taup=1.0,ntwr=500,
> ipol=0,igb=0,
> itgtmd=1,tgtmdfrc=0.005,ntr=0,tgtfitmask=":14,48,58,60,93,101,134,160,214-217",tgtrmsmask=":14,48,58,60,93,101,134,160,214-217"
> /
> &wt type='TGTRMSD', istep1=0,istep2=10000000,
> value1=0.0, value2=0.0
> /
> &wt type='END'
> /
> Thank you very much!
> Xiaodong
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Received on Fri Jan 15 2021 - 09:30:02 PST
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