How do you determine the Pull Direction for a GROMACS umbrella sampling simulation to generate the m

User discussions
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GROMACS version: 2023.2
GROMACS modification: No

I am trying to calculate the free energy between a protein and aptamer using GROMACS. Literature has indicated that one of the best way to do so is by performing an umbrella sampling MD simulation that involves a non-equilibrium pulling simulation that pulls the protein and aptamer apart. I have been running these simulations on certain protein-aptamer complexes but some of the free energy values that I am getting do not match the experimental free energy values from biology experiments. I am thinking that perhaps the pulling direction that I chose was not the best pulling direction. How do I determine the best/correct pulling direction?

Furthermore, what are the common sources of error when performing these umbrella sampling simulations? How do I make my simulations more accurate?

I am essentially using the procedure in this tutorial Umbrella Sampling by Justin A. Lemkul, Ph.D., Virginia Tech Department of Biochemistry, except I am performing it on a protein-aptamer complex.

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Please check out our latest GROMACS tutorials for additional information: new GROMACS tutorials.
** You might also want to explore this link: Potential of mean force using AWH method — GROMACS tutorials https://tutorials.gromacs.org documentation

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When I am running these tutorials, how do I know that I have run it correctly and that the results I am getting make sense in the context of the simulation parameters?