Off topic, but where can I find information about how to attend the Amber
meeting, and future meetings? It doesn't look like there's much info online
about it.
Regards,
Skanda
On Fri, Feb 23, 2024 at 1:04 PM Darrin York via AMBER <amber.ambermd.org>
wrote:
> Hi Helmut and Dave,
>
> My group has developed and been testing lambda-dependent restraints that
> Tai-Sung Lee has implemented in pmemd.cuda, and if we get it fully
> validated, it will be integrated into the next Amber24 release. These
> lambda-dependent restraints have been used to implement more efficient
> Boresch-type restraints used to restrain ligands in their
> non-interacting dummy state to remain bound to protein targets in
> absolute binding free energy (ABFE) calculations. Paper is forthcoming
> - Abir Ganguly may talk about this next week at the Amber meeting.
>
> Note: In an ABFE simulation, one transforms a real ligand state that is
> interacting with the protein and solvent into a non-interacting "dummy"
> state. Unrestrained, such a non-interacting dummy state of the ligand
> would drift out of the binding pocket and disrupt replica exchange (and
> ACES). Hence, on can use a special set of restraints, designated
> "Boresch-type restraints" between the non-interacting ligand and the
> protein that has the special property that they do not introduce a net
> potential of mean force on any of the protein atoms (and thus will
> produce the same protein ensemble as is the restraints were not present
> at all). An analytic correction can be made for the free energy of
> imposing the Boresch-type restraints on the non-interacting dummy state
> of the ligand (to remove the free energy contribution of restraining
> it), but this is not rigorous to apply to the interacting (real) state
> of the ligand. Hence, if one uses a fixed (NOT lambda-dependent) set of
> restraints throughout an alchemical transformation, one would have to do
> a separate explicit sets of simulations to obtain the free energy
> contribution of releasing ("loosening") the restraints from the
> interacting ligand.
>
> An alternative approach is to not have any restraints on the interacting
> ligand at all (as it will stay bound to the protein due to these
> interactions), and only introduce the lambda-dependent Boresch-type
> restraints as the ligand transforms into the non-interacting dummy
> state. In this way one avoids the need for a separate sets of
> simulations altogether.
>
> The implementation of lambda-dependent restraints is one of several very
> useful new features for alchemical free energy simulations that will be
> part of Amber24.
>
> As an alternative, one can conduct a series of simulations using
> different restraint force constants (with or without REMD) and use
> parameter interpolation thermodynamic integration in a post-processing
> step for the analysis - see:
>
> A GPU-Accelerated Parameter Interpolation Thermodynamic Integration Free
> Energy Method
> Timothy J. Giese, Darrin M. York
> J. Chem. Theory Comput. (2018) 14, 1564–1582
> DOI: 10.1021/acs.jctc.7b01175
>
> Dave's caution about potential caveats are certainly on point. I hope
> this is helpful.
>
> best wishes,
>
> Darrin York
>
> On 2/23/24 14:15, David A Case via AMBER wrote:
> > On Thu, Feb 22, 2024, Helmut Carter via AMBER wrote:
> >
> >> Subject: Thermodynamic Integration of Loosening Restraints
> >>
> >>
> >> I would like to determine the free energy change associated with
> >> loosening
> >> restraints on a small molecule, going from 100 kcal/mol*A^2 to 0.
> >> Because
> >> this alchemical transformation does not involve a change in the molecule
> >> topology, I do not see a straightforward way of doing it in AMBER/pmemd.
> >
> > Some coding would be needed here. Remember that TI basically computes
> > the
> > average of dV/dlambda and various intermediate lambda values. Restraints
> > are computed in ene.F90 (subroutine xconst) in sander. You would need to
> > modify this code to make the restraints lambda-dependent, then compute
> > the
> > average value over a simulation. For your case, you don't need to
> > specify
> > icfe, since there is not need to consider two different prmtop files.
> > You
> > would just run a straightforward simulation and print out (or average
> > on the
> > fly) the required value.
> >
> > (Same idea for pmemd, but I'd try in sander first. If you want GPU
> > acceleration, you would need to code a GPU kernel for that. So, consider
> > exploring the idea on the CPU version first.)
> >
> > A caveat: I've never done this, and I might well be missing something.
> > Certainly, you would need to be careful if there are large
> > conformational changes upon relaxing the restraints -- e.g. if the small
> > molecule dissocates from the protein when the restraints go to zero.
> >
> > Also: are you sure that what you describe is what you really want to
> > do? The
> > "usual" procedure is to decouple the small molecule from the rest of the
> > system while restraints are still in place. After that, you can
> > compute the
> > free energy of releasing the restraints analytically, since the small
> > molecule no longer interacts with the rest of the system. But your
> > approach
> > might have some advantages; I'm just suggesting that you think carefully
> > about what you will do with your result once you obtain it.
> >
> > ...good luck....dac
> >
> >
> > _______________________________________________
> > AMBER mailing list
> > AMBER.ambermd.org
> > http://lists.ambermd.org/mailman/listinfo/amber
> >
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Fri Feb 23 2024 - 14:30:02 PST
