Hi Niel
Thank you so much for your suggestions. It is very informative.
Best,
Rehan
On Mon, May 31, 2021 at 11:38 PM Niel Henriksen <shireham.gmail.com> wrote:
> 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 Tue Jun 01 2021 - 10:00:03 PDT
