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 - 15:30:02 PST
