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

[Abhi Acharya]

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?

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?

Any help would be appreciated. Thanks in advance.

Regards,
Abhishek Acharya