Hi Rehan,
A couple of suggestions ....
1) APR is usually not ideal for a buried binding pocket. Since APR requires
a physical pathway to connect the free energy endpoints (ie, bound -->
unbound), there can be major sampling problems if a large conformational
change is required to proceed along the pathway. The approach generally
works best for cases when at least part of the ligand has some solvent
exposure in the bound state (e.g., cyclodextrin and its ligands). It is a
little hard to tell from your screenshot, but I suspect your protein/ligand
system will at least be challenging, if not near impossible. Here's an
example of using APR on a protein/ligand system which required some careful
tuning to be reliable:
https://pubs.acs.org/doi/abs/10.1021/acs.jctc.7b00275
2) You might consider an alchemical approach (e.g. thermodynamic
integration, FEP, etc) if your pocket is as buried as it seems.
3) If you are really convinced that APR is the right approach, I definitely
recommend first getting comfortable using it with a simple model system
like cyclodextrin or cucurbituril. The simulations will run quickly which
will allow you to quickly troubleshoot any problems you might encounter.
Good luck!
--Niel
On Sun, May 30, 2021 at 12:39 PM Rana Rehan Khalid <ray.binm.gmail.com>
wrote:
> Dear AMBER Users
>
> I have an inhibitor-bound complex, I want to study the ligand transition
> states through umbrella sampling, attachment-pul-release approach. In APR,
> we pull the guest gradually away from the host by imposing external
> restraint, generating different RC/CV, and then those RC/CV run in
> different windows.
>
> My question is if during pulling guest make clash with side-chain atoms of
> residue, (or we have we less space within the pocket to pull ligand away)
> then how can we apply the umbrella or APR approach. I am also attaching the
> image of my complex in which you can see that two F residues rings are at a
> distance of 4.3A. NOw If I pull this guest away its adenine ring may cause
> a clash with the phenylalanine side chain.
>
> Looking forward to hearing from you.
>
> Best
> Rehan
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Received on Mon May 31 2021 - 21:00:02 PDT
