[gmx-users] Obtaining PMF for change in domain position

Abhi Acharya abhi117acharya at gmail.com
Tue Dec 30 12:45:19 CET 2014

Abhishek Acharya
Shasara Research Foundation

On Tue, Dec 30, 2014 at 10:42 AM, Justin Lemkul <jalemkul at vt.edu> wrote:

> On 12/29/14 11:34 AM, Abhi Acharya wrote:
>> On Mon, Dec 29, 2014 at 8:59 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>> On 12/29/14 6:57 AM, Abhi Acharya wrote:
>>>  Hello GROMACS Users,
>>>> This is a problem I am facing for the first time. Kindly guide be to the
>>>> best options.
>>>> I have a protein which has two large domains connected by a flexible
>>>> linker
>>>> peptide (~10 aa). The two domains seem to interact with each other and
>>>> have
>>>> been crystallized in three different conformations. I want to calculate
>>>> the
>>>> change in binding energy of the two domains wrt change in their relative
>>>> position, i.e. keeping position of one domain constant what is change in
>>>> binding energy as the other domain moves from conformation 1, through
>>>> conformation 2 to finally, conformation 3. What is the best way to do
>>>> so?
>>>>  You need to describe what these three conformations are.  Do they
>>> involve
>>> rotations of the domains with respect to one another, or is it a simple
>>> linear distance that varies?
>> Yes, there are significant rotations+translations along different axes
>> involved which makes it challenging. Is there a way to model such
>> movements
>> using the pull code?
> Perhaps the enforced rotation options can be useful here.

I had a brief look at these options; seem to be appropriate for my problem.
I will try them first

>>> At first, I considered using umbrella sampling to address the problem.
>>> Here
>>>> too, I was not sure how to write a pull code for such a complex reaction
>>>> coordinate. Also, even if I can generate the conformations, what would
>>>> be
>>>> the ideal number of windows that would be needed to correctly generate a
>>>> PMF ? My feeling is it would be a large number, but again it just a
>>>> guess.
>>>> Is there is a better way than this?
>>>>  Hard to know a priori.  You may need some trial and error here, but
>>> with
>>> umbrella sampling it's trivial to just go back and add windows, since the
>>> simulations are still all independent of one another.
>> My concern is that since the domain movement from initial to final
>> conformation is of about 10 nm, the number of windows required maybe too
>> large. I read that the windows need to be spaced close enough so that each
>> one samples some part of the next window. My system is also very large
>> (200K atoms), so it seems to be computationally very expensive.
> The number of windows needed is largely a function of the force constant,
> e.g. how strong the biasing potential is.  But that's also a function of
> how strong the interactions are that are intrinsic to the system.
>  I was just now thinking to reduce the problem to  conducting umbrella
>> sampling for each conformation, simply using COM distance of the two
>> domains as the reaction coordinate to obtain the PMF in each case. From
>> the
>> PMF, the binding energy of the domains in each conformation can be obtain.
>> This will allow me to circumvent the complications introduced by domain
>> rotations and maybe reduce the number of simulations required a bit . Will
>> this be a correct approach?
> Possibly, but COM distance can be a degenerate measure in the case of
> rotation.  The PLUMED plugin may be useful here rather than standard
> Gromacs options, otherwise try to find an example in the literature and
> follow a known procedure.

I was suggested the same by someone else too, just thought to try options
in gromacs before I try something unknown to me. I would try PLUMED in case
the enforced rotations don't work.

Thank you for the suggestions, always appreciated.


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