What is membrane-partitioning free energy? Can it be simulated?

Question

Firstly, is there a strict definition of the "membrane-partitioning free energy"? It is banded around in membrane biology, but I have never seen it strictly defined. The only non-scholarly site that google shows is this Q&A on quora, and the answer there even has ambiguity in what is defined as partitioning in the membrane. This seems wholly unclear.

Furthermore, is it possible to study free energy changes upon partitioning in GROMACS, or with any other molecular dynamics simulations? If not, what are the methods I would need to use to determine the free energy of partitioning?

Links and citations for further reading on this topic are encouraged.

Answer 1

In the biological context, membrane-partitioning is usually referring to the stage in which the transmembrane-destined region of a protein moves from interacting with the water, to interact with the interface of the membrane.

In the diagram below showing a four step thermodynamic cycle, the partitioning free energy can be referred to as-is ΔG_wiu in terms of free energy where w is water, i is the interface, and u is unfolded. The image comes from the same paper that introduced the famous Wimley and White octanol-interface scale from 1999.

Note that in a more recent 2015 article, they comment that the partitioning phase ΔG_wiu is generally the only experimentally accessible step. With that in mind, simulating ΔG_wif where f is the folded helix becomes necessary. This 2014 Nature Comms paper use folding-partitioning molecular dynamics simulations to estimate the free energies that are experimentally inaccessible. They used Gomacs 4.5. In fact, a study using a simulation from 2005 suggests that folding isn't necessarily required for insertion of the helices.

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Note that all the information here is behind a paywall. Feel free to ask me for clarification or expansion in the comments.