Re: [AMBER] Questions about TI

From: <>
Date: Wed, 18 Nov 2015 02:17:43 -0600

Hi Pengfei,

On Thu, Nov 12, 2015 at 8:45 AM, lipengfei_mail <>

> Dear all,
> When I do TI calculations, I encountered some questions as below:
> 1.In the "Final Remarks"part of AMBER TI Tutorial A9, there is a word
> that"The author of this tutorial has found that the one–step protocol may
> fail in some circumstances".
> What does it mean? Could you give me some examples in which one-step
> protocol may fail?

   Are there some rules about how to choose one-step or three-step protocol?

Here are some one-step protocol papers:

J. Chem. Phys. 127, 214108 (2007); doi: 10.1063/1.2799191


JCC. DOI: 10.1002/jcc.21909

We just have another accepted article discussed about this topic. I am
more than happy to keep you posted when it is available online (hopefully
in 2-3 weeks).

In brief, if computational resources are not a limitation, three-step TI is
recommended since it should converge better. Vice versa. If you run a
three-step/one-step TI, you should make a plot of final dG along MD time
frame. This simple method could make sure the dG results are converged.
This is particularly important for one-step TI since the one-step TI might
not converged as well as three-step TI.

> 2.After I accomplished this tutorial, I got much the same results as the
> tutorial gave.
> But I think that for ligands, ΔGligands (solution)= -38.99 kcal/mol,
> this seems unreasonable.
> As a rough estimation, the solvation free energy for benzene and phenol
> are 0.59 and -4.68 kcal/mol,respectively.
> The energy variation from benzene to phenol in gas phase is about
> -23.22 kcal/mol.
> Then the total energy variation from benzene to phenol in the solvation
> can be estamitated as dG=-0.59-4.68 -23.22=-28.49 kcal/mol,
> which has large difference with the result given out by the A9
> tutorial (-38.99 kcal/mol ).

How many windows and how long the simulation did you run? To get converged
and accurate results, longer TI simulation (usually > 1-3 ns) and and more
windows (>6-11 windows) might be required. For such a 'light' system, I
would probably run 21 windows or more.

> 3.In the course of decharge, if only decharge the O1 and H6 of benzene
> where crgmask = ':1.O1,H6',
> the rest atoms of benzene for MD will be charged which is obviously
> unreasonable.
> One way is to set the crgmask=‘:1' . But if 1 refers to a large ligand,
> then there is less overlap between the initial and final state.

crgmask = ':1.O1,H6' is correct. If we choose crgmask=‘:1', the TI
transformation region is too large and can hardly converge.

   Could any advice be given out about the two choices as above or some
> better ways instead?
> Best,
> Thank you very much !
> --
> -------------------------------------------------------------------------
> Pengfei Li & Fengjiao Liu
> _______________________________________________
> AMBER mailing list

Pin-Chih Su (Henry Su)
Center for Pharmaceutical Biotechnology (MC 870)
College of Pharmacy, University of Illinois at Chicago
900 South Ashland Avenue, Room 1052
Chicago, IL 60607-7173
office      312-996-5388
fax         312-413-9303
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Received on Wed Nov 18 2015 - 00:30:04 PST
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