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Reviewer 1: Stuart Edelstein

Posted by PLOS_CompBiol on 28 Jun 2013 at 09:42 GMT

[This is a review of the original version. See Text S1 for the version history. The authors’ responses are included in line and are reflected in the published version.]

This text provides an excellent overview of cooperative binding as it applies principally to multi-site proteins. However, for clarity and consistency a number of points could be clarified.

1. Concerning the Bohr effect, what is stated is correction, but more commonly the Bohr effect is associated directly with the pH dependence of oxygen binding curves for hemoglobin.

Response: It is my understanding that the Bohr effect refers to the effect of both pH and CO2 concentration on oxygen binding. To reflect this, I have altered the sentence to read "This latter phenomenon, together with the observation that hemoglobin's affinity for oxygen increases with increasing pH, is known as the Bohr effect."

2. The discussion of the Hill equation is fine, but concerning the Hill plot, the intercept at log [Y/(1-) = 0 gives log (Kd) directly, not - log (Kd), (as shown correctly in Figure 5).

Response: Yes, of course. This was a fossil from a former figure and a different formulation.

3. For the Klotz equation the series that includes the statistical factors n, (n-1)/2 , …1/n provides enough information to interpolate the entire series, but for some readers unfamiliar with such series it would be help to note that each element is defined by : (n – i + 1)/i

Response: We added an explanation in parenthesis.

4. For the KNF equation which reproduces equation 13 in the 1966 paper, the initial (1/4) does not appear in the original version and in fact the relationship to the Pauling equation would be clearer if the numerator were divided by 4.

Response: We initially chose this form to relate Ybar the equation 13 of the 1966 paper, which presented Ns, the number of bound site, equals to 4 times Ybar. We agree that the simplification suggested by Prof Edelstein is better, and we changed the formula accordingly.

5. For general usage it is not necessary to capitalize Apartate for aspartate trans-carbamylase, nor Lambda for lambda phage.

Response: Fixed

6. The heading Ionic Channels would be more conventional if presented simply as Ion Channels.

Response: Fixed

7. It was not obvious why some references include superscripted links a and b for returns to the text and other do not. I suspected they were for proper names cited in the text, but if so this rule is not applied consistently.

Response: These references are created automatically by mediawiki. When several citations are made to a given reference, this references links back to the citations though those superscripts (an advantage of webpages over classical papers).

No competing interests declared.