I'm not an expert on the modern softcore potentials or things that can go
wrong in TI, but I do think it's helpful to make sure the system behaves
well in md before doing TI. Also check to make sure the ion model that you
chose is compatible with the water model. Mismatches can cause such binding
issues.
If the ion is only there to have charge neutrality on both ends, perhaps a
restraint to keep it away could be useful. But do make sure it's ok in md
first. I haven't seen glu forming such strong interactions with Na.
On Tue, Mar 7, 2023, 6:14 PM He, Amy <he.1768.buckeyemail.osu.edu> wrote:
> Hi Dr. Simmerling,
>
>
>
> I did the (pre-production) equilibration runs with soft core potential,
> individually for each window. I guess the binding can occur in normal MD,
> although I didn’t do such simulation for dipeptides. I can try that and let
> you know how it goes. It would be meaningful to get the equilibrium
> geometry from normal MD, to show how much distortion is caused by the
> softcore potential.
>
>
>
> In regular MDs, we have seen such binding also in binding pocket of some
> proteins, if the pocket has a directional electrostatic field. The
> counterion could move down the gradient and eventually binds to a GLU, and
> it’s hard to dissociate.
>
>
>
> Thanks again for your kind replies, and I would really appreciate it if
> you have any further comments/suggestions.
>
>
>
> Bests,
>
> Amy
>
>
>
> *From: *Carlos Simmerling <carlos.simmerling.gmail.com>
> *Date: *Tuesday, March 7, 2023 at 6:07 PM
> *To: *He, Amy <he.1768.buckeyemail.osu.edu>
> *Cc: *AMBER Mailing List <amber.ambermd.org>
> *Subject: *Re: [AMBER] How to shield charged side chain from ion binding
> / would you transform a counterion in TI simulations?
>
> I'm still uncertain if this happens for you in normal md (no TI) or only
> TI. Can you clarify? On Tue, Mar 7, 2023, 5: 36 PM He, Amy <he. 1768@
> buckeyemail. osu. edu> wrote: Hi Dr. Simmerling, Thanks a lot for your
> insightful comments.
>
> I'm still uncertain if this happens for you in normal md (no TI) or only
> TI. Can you clarify?
>
>
>
> On Tue, Mar 7, 2023, 5:36 PM He, Amy <he.1768.buckeyemail.osu.edu> wrote:
>
> Hi Dr. Simmerling,
>
>
>
> Thanks a lot for your insightful comments. I have a Na+ that binds to GLU
> during the MD simulation, and then the DV/DL I got in TI becomes extremely
> high for the window when this Na+ has almost disappeared.
>
>
>
> do you have these ion binding problems in MD of the endpoint state, or
> only during TI?
>
> ----------
>
> I feel that the binding is possible (and therefore inevitable) for regular
> and MD-based TI simulations, if Na+ are added and GLU is completely
> exposed. As we extend the simulation time, we will eventually see Na+ bind
> to GLU.
>
>
>
> is the ion that is binding too much the Na+ that you are disappearing?
> does the binding happen when the Na is nearly disappeared?
>
> ----------
>
> That is a truly very helpful point. Yes, the bound ion happens to be the
> one that is disappearing. I think this is ok conceptually since the
> transformation now becomes GLH -> GLU Na+.
>
>
>
> The binding is seen throughout the 9 windows I built in between the
> initial and the end state. But only the DV/DL at lambda = 0.9 (Na+ almost
> fully appeared) blew up! So I feel this might be something we can work on
> the softcore potential.
>
>
>
> it's likely that removing the vdw on the Na while it still has a charge
> will not be easy, and need some special treatment with softcore functions.
>
> ----------
>
> Yes I’m not very sure whether transforming the ions has been tested with
> the soft core potential.. From what I saw, the large positive DV/DL is
> mainly made up by the VDW interaction.
>
>
>
> Please see the printed out DV/DL for lambda = 0.9 (the problematic one,
> Na+ almost fully appeared):
>
> 1-4 NB = -0.1884 1-4 EEL = 15.8431 VDWAALS =
> 3442.0543
>
> EELEC = -1074.5474 EHBOND = 0.0000 RESTRAINT =
> 0.0000
>
> DV/DL = 2381.6957
>
>
>
> And its adjacent window lambda = 0.8 (large VDW but… ok):
>
> 1-4 NB = -0.1358 1-4 EEL = 16.2379 VDWAALS =
> 421.6194
>
> EELEC = -382.0313 EHBOND = 0.0000 RESTRAINT =
> 0.0000
>
> DV/DL = 54.3296
>
>
>
> For lamda = 0.1 (almost no Na+):
>
> 1-4 NB = 0.0858 1-4 EEL = 17.2296 VDWAALS =
> -2.8622
>
> EELEC = -19.2770 EHBOND = 0.0000 RESTRAINT =
> 0.0000
>
> DV/DL = -5.3522
>
>
>
> Maybe instead of making a Na+ in a single step, I could turn on the vdw
> first (so it’s aware of the proper distance before pulling Na+ closer),
> then charging it. That seems to be the traditional way of doing the
> alchemical transformation although that’s against the spirit of the
> softcore potential..
>
>
>
> Thanks again for your time and response. I really appreciate it.
>
>
>
> Many Thanks,
>
> Amy
>
>
>
>
>
> *From: *Carlos Simmerling <carlos.simmerling.gmail.com>
> *Date: *Tuesday, March 7, 2023 at 3:40 PM
> *To: *He, Amy <he.1768.buckeyemail.osu.edu>, AMBER Mailing List <
> amber.ambermd.org>
> *Subject: *Re: [AMBER] How to shield charged side chain from ion binding
> / would you transform a counterion in TI simulations?
>
> do you have these ion binding problems in MD of the endpoint state, or
> only during TI? is the ion that is binding too much the Na+ that you are
> disappearing? does the binding happen when the Na is nearly disappeared?
> these details will be important
>
> do you have these ion binding problems in MD of the endpoint state, or
> only during TI?
>
> is the ion that is binding too much the Na+ that you are disappearing?
> does the binding happen when the Na is nearly disappeared?
>
> these details will be important to understanding the problem. it's
> likely that removing the vdw on the Na while it still has a charge will not
> be easy, and need some special treatment with softcore functions.
>
>
>
> On Tue, Mar 7, 2023 at 1:46 PM He, Amy via AMBER <amber.ambermd.org>
> wrote:
>
> Dear Amber community,
>
> I am running TI simulations with sander.MPI in Amber 20. My systems are
> all made of a simple dipeptide in explicit TIP3P waters + ions. These
> simulations are intended for baseline corrections of the TI simulations I
> have done for the protein systems, in which I transform the charge state of
> residues.
>
> I have a working TI protocol for the protein systems with similar setups.
> But I am having trouble getting reasonable DV/DL for these simple
> dipeptides. I got some very large (over 3000 kcal/mol) DV/DL because I
> cannot shield the charged side chain from binding with a counterion..
>
> Please see more details below about the simulation setups:
>
> The dipeptide is a glutamate residue capped on both sides: NME-GLU-ACE.
> The protonated form is: NME-GLH-ACE
>
> The initial state contains: NME-GLU-ACE, 4 Na+, 3 Cl-, about 23000 TIP3P
> waters
> The end state contains: NME-GLH-ACE, 3 Na+, 3 Cl-, same number of waters
>
> The atoms that undergo alchemical transformation are:
> OE2 and one Na+ in the initial state
> OE2 and HE2 in the end state
>
> I would really appreciate any comments/suggestions regarding this… Is it
> just a bad idea to transform a counterion (even though I have that delta G
> canceled in my thermodynamic cycle..)? Should I just exclude all Na+ to
> avoid the binding?
>
>
> Many Thanks,
> Amy
>
>
> --
> Amy He
> Chemistry Graduate Teaching Assistant
> Hadad Research Group
> Ohio State University
> he.1768.osu.edu<mailto:he.1768.osu.edu>
>
>
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Received on Tue Mar 07 2023 - 15:30:03 PST
