[gmx-users] The Rationality of Position Restrain in Umbrella Sampling

[Jason Zhu]

Dear Justin,

Thank you for your prompt response. Your information is very helpful.

Now I understand that the position restrain is used to to mimic the
stability of a much larger structure of A-beta fibrils and make the pulling
direction coincident with the fibril axis.

The system I am studying is a complex of two same molecules (in linear
shapes). I tried to separate them and calculate the binding free energy. My
question is whether the free energy or energy curve is dependent of pulling
direction with respect to the complex orientation. If I removed the
position restrain, the two linear molecules preferred to rotate first until
their interface parallel to the pulling direction and slide away from each
other. Is it reasonable and valid to get the correct binding free energy
and energy curve? Do I need change the initial orientation to the preferred
one?

Best,
Wenpeng Zhu

On 5/2/17 9:54 AM, Jason Zhu wrote:
> Dear All,
>
> I am modeling the free binding energy between two molecules following the
> Gromacs Tutorial 3: Umbrella Sampling (
>
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html
> ).
>
> In this tutorial, the Chain_B of proteins is fixed as an immobile
reference
> by position restrain during not only the stage of Steered MD but also the
> stage of Umbrella Sampling.
>
> I am wondering what the rationality of the position restrain is for the
> calculation of free energy. Does this reduce of degree of freedom due to
> the position restrain have any artificial influence on the calculated free
> energy?
>

Please read the paper I linked from the tutorial, and references therein,
which
explain this rather unique case.  Normally one does not need additional
restraints during US.

-Justin

> Why don't we just use "COM motion removal" method to fix the COM of the
> protein complex and use pulling method to separate the Chain_A from other
> protein chains? Is it because of the excessively strong binding between
> them? If we use position restrain, do we need to make some corrections to
> the calculated binding free energy, just like the below paper?
>
> Boresch, S., Tettinger, F., Leitgeb, M., and Karplus, M. (2003) Absolute
> binding free energies: A quantitative approach for their calculation. J.
> Phys. Chem. A 107, 9535?9551
> (http://pubs.acs.org/doi/abs/10.1021/jp0217839)
>
> Best,
> Wenpeng Zhu
>

--
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==================================================


------------------------------

2017-05-02 9:54 GMT-04:00 Jason Zhu <jasonzhu925 at gmail.com>:

> Dear All,
>
> I am modeling the free binding energy between two molecules following the
> Gromacs Tutorial 3: Umbrella Sampling (http://www.bevanlab.biochem.
> vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html).
>
> In this tutorial, the Chain_B of proteins is fixed as an immobile
> reference by position restrain during not only the stage of Steered MD but
> also the stage of Umbrella Sampling.
>
> I am wondering what the rationality of the position restrain is for the
> calculation of free energy. Does this reduce of degree of freedom due to
> the position restrain have any artificial influence on the calculated free
> energy?
>
> Why don't we just use "COM motion removal" method to fix the COM of the
> protein complex and use pulling method to separate the Chain_A from other
> protein chains? Is it because of the excessively strong binding between
> them? If we use position restrain, do we need to make some corrections to
> the calculated binding free energy, just like the below paper?
>
> Boresch, S., Tettinger, F., Leitgeb, M., and Karplus, M. (2003) Absolute
> binding free energies: A quantitative approach for their calculation. J.
> Phys. Chem. A 107, 9535–9551
> (http://pubs.acs.org/doi/abs/10.1021/jp0217839)
>
> Best,
> Wenpeng Zhu
>