Affinity and Correlation in DNA
Round 1
Reviewer 1 Report
The article presents the great job on statistical studying of interactions in DNA.
The authors deeply analyzed the subject.
The article should be accepted in the present form.
Author Response
Nothing to add.
Reviewer 2 Report
The manuscript by Giovanni Villani reports a theoretical study on the correlation of DNA based on statistical analysis and quantum chemical calculations. The author provides very interesting information about the relationship between two successive amino acids in proteins and two consecutive base pairs in all the DNA sequences studied. There is only a major point that has to be addressed before I can recommend the paper for publication.
Major issue:
- The paper lacks of some computational details making difficult to judge the quality of the MP2 results. For instance:
(i) Are the geometries reoptimized after the replacement of the NH2 and CH3 groups? (Page 5) It is written that the geometries are taken from previous references but it is not clear whether they are or not reoptimized. Furthermore, these substitutions could affect the stacking energy, especially the NH2 group in some cases somehow interacts through hydrogen bond (HB) with the stacked base enhancing the stacking, so changing this by an H atom could not be a good approach. Has the author checked if this is the case?
(ii) How are the energies for the monomer and stacked dinucleotide obtained? In gas phase? in solution?
(iii) For the duplex, is the stabilization energy coming from the formation of the Watson-Crick pair considered? By estimation of the HB?
(iv) Last but not least, I have concerns about the estimation of the stacked energy considering only one dinucleotide. In a given single strand, there are several XpX or XpY steps that have different stacking degrees, in other words, not all the CpG steps are equally stacked… Has the author checked how this energy is affected when considering a sampling of steps coming for instance from molecular dynamics? Or just considering some limit situations? This could be even more essential in the duplex.
Minor issues:
(i) Page 8, line 267: two references 18 (as superscript) and 40 in brackets are given. Are both correct?
(ii) In my opinion the summary of the literature in page 11 could be reduced.
Author Response
Dear,
Following your suggestions, I modified the paper as follow.
- To answer the main issue “The paper lacks of some computational details making difficult to judge the quality of the MP2 results”, I added at pag. 8:
“The geometries of the base pair dimers ref. 37 were obtained by optimising the gas phase geometry at the MP2/cc-pVTZ level of CS symmetry-bound theory, and this symmetry constraint is necessary for idealised planar base pairs, preventing a potential non-planarity due to the pyramidalization of the amino group. In addition, to create idealized base pair geometries, they chose the "natural" arrangement of B-DNA using a 36° helical twist and a 0° helix.
Our results on modified dimers are also in the gas phase and in the idealized approach, but we reduced the base set from cc-pVTZ to cc-pVDZ and did not perform a re-optimization of the geometries. Our goal, in fact, is only to obtain an average energy value difference for two adjacent base-pairs X and Y (with X≠Y) and the differences between the specific dimers are estimated to be greater than those due to these approximations.
In any case, all inter- and intra-strand interactions are included in our calculations, as in the aforementioned previous study. Also, as mentioned in ref. 37, these systems are not very sensitive to small differences in geometries since the base pair stacking energy corresponds to the low energy conformational region sampled by the thermal motions in a double helix B-DNA.”
- To answer the Minor issues “(i) Page 8, line 267: two references 18 (as superscript) and 40 in brackets are given. Are both correct? (ii) In my opinion the summary of the literature in page 11 could be reduced”, (i) I confirmed the two references and (ii) I deleted at pag. 16:
The mechanism of evolution of a cell's genetic code works to optimize its functions, part of which is described by the information function. A biological interpretation of the results obtained by these authors is the following proposed by them. In general, the information function reaches a maximum when the system it represents has a random distribution, but, if order formation is involved, we must expect the information function to decrease. If we apply this concept to a biological system, it could be argued that, before the formation of living systems organized in cells, the information function of the genetic code had a maximum value, corresponding to a random distribution of the elements.
Best regards
Giovanni Villani
Author Response File: 
Author Response.docx
Round 2
Reviewer 2 Report
Line 239 "base set " should be "basis set"
