On May 22, 2014, at 6:07 PM, Thomas Cheatham <tec3.utah.edu> wrote:
>
>> To add on to Soumendranath's comment, the only time you should _ever_
>> add counterions is when you are running a system in explicit solvent.
>> If this is your complex topology file for MM/PBSA calculations, salt
>> effects are taken into account with a Debye-Huckel parameter for GB or
>> explicitly in the Poisson-Boltzmann equation. Explicit counterions
>> should not be used here.
>
> I disagree with this, at least in the case of MM-PBSA/GBSA, since
> sometimes explicit ions and/or water may be desirable, especially if they
> form specific interactions with the solute. The implicit ion models do
> not accurately capture these types of ion/water interactions. However I
> do agree that including ions in implicit solvent MD simulations is not
> recommended.
I will concede your point for structurally important ions or water molecules that do not behave like the bulk solvent or general ionic atmosphere around the solute (it's these continuum properties that the implicit solvent models and their salt corrections aim to model). I would be curious to see systematic studies where implicit solvent parameters are optimized for ions (at least for the various GB models).
None of these use cases cover adding ions simply to neutralize a species -- that is a bad idea for any implicit solvent model.
Thanks for keeping me honest,
Jason
P.S. For structurally important ions, perhaps 3D-RISM is the way to go, where theoretically the continuum model _should_ be able to capture the non-bulk behavior of structurally important ions.
>
> Two examples where explicit inclusion of ions and/or water improve the
> results are:
>
> (1) Energetic analysis of G-quadruplex structures which is effectively
> misleading/impossible if the ions in the channel are not included.
>
> R Stefl, TE Cheatham, III, N Spackova, E Fadrna, I Berger, J Koca,
> and J Sponer. “Formation pathways of a guanine-quadruplex DNA revealed
> by molecular dynamics and thermodynamical analysis of the substates.”
> Biophys. J. 85, 1787-1804 (2003).
>
> X Cang, J Sponer, and TE Cheatham, III. “Explaining the varied
> glycosidic conformational, G-tract length and sequence preferences for
> anti-parallel G-quadruplexes.” Nuc. Acids Res. 39, 4499-4512 (2011).
>
> X Cang, J Sponer, and TE Cheatham, III. “Insight into G-DNA
> structural polymorphism and folding from sequence and loop connectivity
> through free energy analysis.” J. Amer. Chem. Soc. 133, 14270-14279
> (2011).
>
> (2) Study of drugs binding in the minor groove of DNA where inclusion of
> bound water "helped".
>
> N Spackova, TE Cheatham, III, F Ryjacek, F Lankas, L van Meervelt,
> P Hobza, and J Sponer. “Molecular dynamics simulations and
> thermodynamics analysis of DNA-drug complexes. Minor groove binding
> between 4’-6-diamino-2-phenylindole and DNA duplexes in solution.” J.
> Amer. Chem. Soc. 125, 1759-1769 (2003).
>
>
> More recently, other groups have also played with post-processing MD
> trajectory energy analysis including explicit water or ions.
>
> Zhu YL, Beroza P, Artis DR. "Including explicit water molecules as part
> of the protein structure in MM/PBSA calculations." J Chem Inf Model.
> 2014 Feb 24;54(2):462-9.
>
> Wong S, Amaro RE, McCammon JA. "MM-PBSA Captures Key Role of
> Intercalating Water Molecules at a Protein-Protein Interface."
> J Chem Theory Comput. 2009 Feb 10;5(2):422-429.
>
> However I will note that this approach is a complex/advanced use case that
> requires strong knowledge of the underlying methods/code and requires
> significant care. For example, you have to make sure your GB and/or PB
> parameters for the ions give accurate free energies of solvation. Also,
> you cannot compare systems with different net-charges.
>
> --tec3.utah.edu
>
> p.s. an alternative to MM-PBSA/GBSA is to look at raw potential energies
> (assuming equivalent number of ions/solvent). Soon coming ASAP will be
> our paper describing this in the context of highly charged inhibitors
> interacting with RNA.
>
> NM Henriksen, Hamed Hayatshahi, DR Davis, and TE Cheatham, III.
> “Structural and energetic analysis of 2-aminobenzimidazole inhibitors in
> complex with the hepatitis C virus IRES RNA using molecular dynamics
> simulations.” J. Chem. Info. Model. [in press] (2014)._______________________________________________
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--
Jason M. Swails
BioMaPS,
Rutgers University
Postdoctoral Researcher
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Received on Thu May 22 2014 - 19:30:02 PDT
