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I am reading a chapter on protein stability. One section outlines the role of salt bridges or ion pairs in the stability of a protein. The excerpt goes as follows (italization added for emphasis):

The association of two ionic protein groups of opposite charge (e.g., Lys and Asp) is known as an ion pair or a salt bridge. About 75% of the charged residues in proteins are members of ion pairs that are located mostly on the protein surface (Fig. 6-36). Despite the strong electrostatic attraction between the oppositely charged members of an ion pair, these interactions contribute little to the stability of a native protein. This is because the free energy of an ion pair's charge—charge interactions usually fails to compensate for the loss of entropy of the side chains and the loss of solvation free energy when the charged groups form an ion pair. This accounts for the observation that ion pairs are poorly conserved among homologous proteins.

My question is, how does this look visually? I can read it but I am not able to completely understand the physical representation of the ion pair vs loss of entropy and solvation free energy.

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  • $\begingroup$ Would be good if you could provide a ref to the text. Also, consider that generalizations, such as in this case, are to be interpreted with care. What is the particular function of any given ionic pairing interaction? Also, when you have many such interactions the effects might be synergistic. $\endgroup$
    – Buck Thorn ♦
    Commented Nov 21, 2021 at 12:32

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[OP] I am not able to completely understand the physical representation of the ion pair vs loss of entropy and solvation free energy

In an ion pair, two amino acid side chains are in proximity. This means they have limited range of motion compared to side chains on the surface of the protein that interact exclusivly with solvent. It also means they are less solvated. If a salt bridge is observed, it means that the Gibbs energy of formation is negative. This could be some combination of entropy and enthalpy contributions.

[textbook] This accounts for the observation that ion pairs are poorly conserved among homologous proteins.

When a specific interaction is crucial for the native structure or the function of the protein, you would expect the responsible amino acids to be found in a set of homologous proteins, i.e. they would be conserved. Here, these structures form but are not crucial, so there is no evolutionary pressure to conserve the ion pairs in the same locations.

[textbook] these interactions contribute little to the stability of a native protein. This is because the free energy of an ion pair's charge—charge interactions usually fails to compensate for the loss of entropy of the side chains and the loss of solvation free energy when the charged groups form an ion pair.

The second sentence is a bit inaccurate. Instead of saying "fails to compensate", it would be better to say "barely compensates". A broader view is offered e.g. in this publication.

My question is, how does this look visually?

Protein structural data shows a static view, so it does not directly visualize conformational freedom. It also does not show all solvation (just water molecules that are ordered or somewhat ordered). In fact, some of the side chains lacking salt bridges will not be visible in a crystal structure because they themselves are disordered; lysine is a frequent example. To see a static but 3D view of the salt bridges in myoglobin mentioned in the textbook, you can view the interactive 3D figures of this short article in Proteopedia. Some of the amino acid side chains are shown in two orientations because they are disordered.

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So they are making a comparison between favorable interactions in the bridged and unbridged form, claiming that these interactions are roughly equal in strength.

For the bridged form, the favorable interaction is just the attraction between a positive ion and a negative ion on different parts of the protein.

For the unbridged form, we no longer have this ion-ion interaction. However, in it's place, these ions can now interact with surrounding solvent molecules, which is also stabilizing. In addition, since the two groups with the ions are no longer linked together, they can move more freely, increasing entropy. This again is favorable energetically.

According to the authors, these effects are roughly equal in magnitude (with the bridged tending to be less favorable, but not impossible), so there isn't a strong preference for the bridged form for proteins with these kinds of charged sites. I would interpret, "poorly conserved" to mean something like 10:90 bridged: unbridged, rather than say 1:999.

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  • $\begingroup$ Is it though? The authors state that the salt bridge itself is not a major stabilizing force because entropy and solvation fight against it. Therefore, "ion pairs are poorly conserved among homologous proteins". In other words, the magnitudes of both opposing forces are different. My question is more of why is that the case. Although correct me if I'm wrong. $\endgroup$
    – Brian Blumberg
    Commented Nov 21, 2021 at 0:46
  • $\begingroup$ @BrianBlumberg if these factors were equal in magnitude, we would expect the ratio of bridged to unbridged to be 50:50. I'm assuming "poorly conserved" would be roughly within this order of magnitude, so even something like 10:90 would mean they have roughly equal energy. If "poorly conserved" is more like 1:999, then I might be interpreting the passage wrong, but I believe it saying the energies in these cases are not too different (so no preference when comparing similar proteins), rather than the bridged being very unstable in comparison. $\endgroup$
    – Tyberius ♦
    Commented Nov 21, 2021 at 1:43
  • $\begingroup$ I think that the assumption the author makes is that if we only consider ion pairs, then the opposing force is greater. In other words, the ion pair is like putting on a seatbelt the wrong way. It might work preventing very slight forces but it'll just unclip if something major occurs (which is often the case in biological systems). So, the bridged form isn't unstable, just that the ion pair does little for the stability. Hopefully, Ph.D. Karsten Theis can explain this (he's edited my post and seems to know quite a bit about biochem). $\endgroup$
    – Brian Blumberg
    Commented Nov 21, 2021 at 2:54

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