Re: [AMBER] MD_Box_size_and_counterions_counting_general_rule

From: Matias Machado <>
Date: Wed, 31 Oct 2018 11:04:29 -0300 (UYT)

Dear Antonio,

It may be worth reading the following recent paper of Karplus:

Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size
eLife 2018 []

In practice the box size is usually chosen to avoid seeing the same molecule through PBC images, so you are simulating a solute in diluted conditions without having crystal artifacts... however representing bulk water in a proper way may be important to correctly describe the hydrophobic/hydrophilic balance in some cases as shown by Karplus...

In case of the ions... notice that counterions alone are supposed to not contribute to the ionic strength as they should be already screened by the solute's charges... so a system with just counterions is supposed to have a zero ionic strength... when you start adding so called coions (salt) then you should take into account the presence of counterions to fit the desired salt concentration

I invite you to read the recent paper of Schmit on that issue:
SLTCAP: A Simple Method for Calculating the Number of Ions Needed for MD Simulation. JCTC 2018 []

Regarding solvent volume for estimating salt concentration... IMAO, if you are simulating a diluted condition (a typical in-vitro experiment as David said), then the volume of the protein should be negligible in comparison to water, but in a typical simulation box this condition is not generally the case (solute volume ~ solvent volume), so what I do is calculating the solvent volume from the number of water molecules in the box and assuming a density of ~1 g/mL at 27°C, instead of using the simulation box volume. In that way, water volume should better represent the water activity (i.e. the water available to do something)...

If you pretend to represent an in-vivo condition, where crowding plays a role, then that's more challenging because the protein volume can't be neglected from the equation an everything becomes very odd... IMAO, I think there is still a gap between the microscopic and macroscopic description of concentration in leaving cells or crowded condition... I mean, what is the real meaning of concentration in such cases? what are experimentalists really measuring?

Any way, ions are still a matter of debate and research in MD...



Researcher at Biomolecular Simulations Lab.
Institut Pasteur de Montevideo | Uruguay

----- Mensaje original -----
De: "David A Case" <>
Para: "AMBER Mailing List" <>
Enviados: Jueves, 25 de Octubre 2018 11:18:59
Asunto: Re: [AMBER] MD_Box_size_and_counterions_counting_general_rule

On Thu, Oct 25, 2018, Antonio Amber Carlesso wrote:
> Is there any general rule to follow regarding the size of the box compared
> to the molecular object(s) investigated?

Commonly, Amber users include enough solvent around a molecular that
that there is at least 12-15 Å between any solute atom and the edge of
the box. This is typically done using the solvateBox or solvateOct
commands in tleap.

This is a compromise between accuracy and speed. It can be worth
experimenting with large box sizes to see what happens.

> In addition, counterions that should be added to reflect “physiologic
> condition”..
> Is there any general rule when it is reasonable to substract the volume of
> the solute from the overall volume and when the volume of the solute can be
> neglected in the overall counterions calculations?

There is no general rule here. Use of "physiologic conditions" might
make sense if you are expecting to compare with studies in cells; for
comparisons to in vitro work, of course, different salt conditions might
be more appropriate.

I generally like to prepare simulations such that the *molal*
concentration of salt is the same as that reported for whatever
experiment seems most relevant. This avoids all questions of the solute
partial molar volume. But if the differences are important to you, you
would really need to use multiple box sizes, and look at the effective
concentrations of ions far from the solute in your simulation. This is
occasionally done with highly charged solutes like nucleic acids, or in
studies where the distribution of ions is being investigated. It is
rarely done if properties of the solute are of greatest importance.


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