On the Molecular Driving Force of Protein–Protein Association
Round 1
Reviewer 1 Report
The manuscript is a contribution from a well-known laboratory. This is a solid study that applied SPT-based computations to unveiling the driving forces in protein-protein interactions. The authors arrive at a conclusion that a decrease in solvent-accessible surface area (SASA) accompanying association of two proteins is the driving force of the process. This conclusion is in line with the previous works from this group that all suggest that compaction as expressed in a decrease in SASA is the origin of molecular events occurring in water. The authors may want to emphasize this point (the generality of their finding which is not confined only to protein-protein association) in their revised manuscript.
Author Response
Referee 1 supported publication of the manuscript and asked for minor-minor changes that have been performed in the revision.
Reviewer 2 Report
The submitted manuscript discussed a classical question: what is the thermodynamic nature of the buried surface area to a protein-protein interface. The authors did a detailed practice on deriving the polar and non-polar terms of the Gibbs free energy difference upon a protein-protein association. However, their conclusion is obvious. The entropy gains by the BASA and its linear correlation to free energy loss have been commonly acknowledged in the field and widely applied empirically to calculate the binding free energy, from earlier works of B. Honig (for example, Nicolas, Windemuth, and Honig. Protein Science 6.6 (1997): 1293-1301) to the so-called MM/PBSA (for example, works by H Gohlke), or the latter developed MM/GBSA method, FoldX and so on. Thus, due to the weakness of innovation in current work, I suggest the authors turning this manuscript into a review paper with credits to other consistent developments and efforts to calculate ΔG, or even ΔΔG since 1990s.
Author Response
Referee 2 stated that the manuscript is well done, but does not provide significant innovation in the field and should be reorganized as a review article. We understand the point raised by Referee 2, but we do not agree because our study is expressly devised to offer a qualitative rationalization of the results obtained by Regan and co-workers in Protein Science 2013, 22, 510-515, reference 7 in the manuscript list. Therefore, we have added some references, as suggested by Referee 2, but we have not turned the paper in a review article.
Reviewer 3 Report
In this paper, the Authors present an analysis of the role of the free energy change on the association of two proteins. There is one plot in the paper that is ∆Gc /WASAc versus WASAc. From this figure, authors concluded that the buried water accessible surface area is related to the decrease in the solvent-excluded volume effect and gain in the translation entropy of water upon solvent formation, which acts as a driving force of protein association.
The paper is publishable after addressing minor comments:
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In the introduction, the importance of protein association study in fibril formation and liquid-liquid phase separation should be added. For example: J. Phys. Chem. Lett. 2021, 12, 37, 9026–9032, Proceedings of the National Academy of Sciences, 118(38), p.e2110995118. Biophysical Journal 120, 1266–1275, April 6, 2021
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Include the equation that gives the ∆Gc as a function of cavity size.
Author Response
Referee 3 supported publication of the manuscript and suggested the addition of some very recent references and of the SPT equation for the calculation of the reversible work of cavity creation in a liquid. We have added the suggested references, but not the SPT equation because it is not useful for the readability of the paper, and it can be found in a lot of published articles, some of them cited in the manuscript.
Round 2
Reviewer 2 Report
The authors made it clear that this work is to provide a qualitative rationalization for the results obtained by Regan and co-workers in Protein Science 2013, 22, 510-515, and have cited the important works in the field that I have suggested. Although its innovation is still not a persuasive reason for its acceptation, overall it is a work nicely done, with a neat research completion and presentation.
