Molecular Modeling Based on Time-Dependent Density Functional Theory (TD-DFT) Applied to the UV-Vis Spectra of Natural Compounds

Round 1

Reviewer 1 Report

I have reviewed the manuscript by Anhaia-Machado et al. on “Molecular modeling based on time-dependent density functional theory (TD-DFT) applied to UV-Vis spectrum of natural compounds”. The authors used DFT and TD-DFT to calculate the UV-Vis spectrum of several potential candidates of photo protector compounds and the results agreed with experimental validation.

I have the following questions/comments on the manuscript, which I think need to be addressed before it can be accepted for publication:

1. Overall, the main context of the manuscript is primarily an application of computational softwares. The compound structures are not very complicated; the methods used are geometry optimization (semi-empirical and DFT level) and frequency domain TD-DFT, which are relatively matured techniques. Thus, some analysis, insights, or novelty need to be highlighted in the results section.

2. On the method side, B3LYP functional is not the latest functional and there are better functionals for organic molecules, for example, M06. Some test on the functional dependence is necessary. Also, the basis set size is not tested, and the authors need to show the influence of changing basis size. If there are correlated methods beyond TD-DFT, for instance, GW+BSE or EOM coupled cluster method, that may be good to benchmark the accuracy of DFT. I think some of these aspects need to be done in order to show the ability of the current approaches.

3. The caption of Figure 5 said “Electronic transitions calculated by TD-DFT”. The HOMO and LUMO are from the static DFT calculations, not from the TD-DFT, is that correct?

4. There are few results from previous theoretical works on these compounds. I think it is necessary to compare some of them with the current work, if a compound has been calculated before.

Author Response

Comments and Suggestions for Authors

I have reviewed the manuscript by Anhaia-Machado et al. on “Molecular modeling based on time-dependent density functional theory (TD-DFT) applied to UV-Vis spectrum of natural compounds”. The authors used DFT and TD-DFT to calculate the UV-Vis spectrum of several potential candidates of photo protector compounds and the results agreed with experimental validation.

I have the following questions/comments on the manuscript, which I think need to be addressed before it can be accepted for publication:

1. Overall, the main context of the manuscript is primarily an application of computational softwares. The compound structures are not very complicated; the methods used are geometry optimization (semi-empirical and DFT level) and frequency domain TD-DFT, which are relatively matured techniques. Thus, some analysis, insights, or novelty need to be highlighted in the results section.

After the construction of the compound's structures in Gaussview 4 [33], they were submitted to conformational analyses in Spartan'14 [34]. The conformational search by the semi-empirical PM6 method was carried out to select, among all possible 3D conformations, the most stable one, which has the lowest energy [40]–[43].

The most stable conformation was subjected to DFT calculations, seeking to understand its energy transitions and perform a vibrational analysis, different studies also used DFT for conformational and energy calculations [44], [45].

For the DFT methods, functional B3LYP and base 6-311+G(d,p) were used, using the implicit solvent methanol (IEFPCM) in Gaussian 09, the functional B3LYP was used because it is a functional already consolidated in the prediction of UV- Vis. Previous studies by the group, by Garcia 2015, also evaluated the effect of different functionals on theoretical UV-vis predictions and the one that had the highest accuracy for organic molecules with photoprotective qualities was B3LYP [14], [15], [39], [41], [46], [47].

2. On the method side, B3LYP functional is not the latest functional and there are better functionals for organic molecules, for example, M06. Some test on the functional dependence is necessary. Also, the basis set size is not tested, and the authors need to show the influence of changing basis size. If there are correlated methods beyond TD-DFT, for instance, GW+BSE or EOM coupled cluster method, that may be good to benchmark the accuracy of DFT. I think some of these aspects need to be done in order to show the ability of the current approaches.

The choice of the B3LYP functional was based on previous results from our group, in which different functionals were evaluated for predicting UV-vis spectra. In this study B3LYP showed the best results, which were validated by experimental data. (Garcia 2015). In addition, the methodology using B3LYP functional is consolidated for application in spectral simulation studies for organic molecules with photoprotective quality (Corrêa et al., 2012)(Basavaraj & Hanagodimath, 2020; Cornard et al., 2005; Garcia et al., 2015; Martin et al., 2017; Trossini et al., 2015).

… the functional B3LYP was used because it is a functional already consolidated in the prediction of UV- Vis. Previous studies by the group, by Garcia 2015, also evaluated the effect of different functionals on theoretical UV-vis predictions and the one that had the highest accuracy for organic molecules with photoprotective qualities was B3LYP [14], [15], [39], [41], [46], [47].

3. The caption of Figure 5 said “Electronic transitions calculated by TD-DFT”. The HOMO and LUMO are from the static DFT calculations, not from the TD-DFT, is that correct?

Thank you for your observation. The caption was corrected, the electronic transitions were indeed calculated by DFT.

4. There are few results from previous theoretical works on these compounds. I think it is necessary to compare some of them with the current work, if a compound has been calculated before.

Thank you for your suggestion, the following paragraph was added to the manuscript.

A comparison amongst the previous theoretical studies and the results obtained in this work showed that the methodologies are convergent. In these studies the galic acid, when assess using the function B3LYP and 6-311+G (d,p) basis, in water (IEFPCM) the absorption peak (λmax) of 275nm, while our study showed 284 nm (3% difference between the results), probably due to the solvent used [47]. For quercetin, the difference between the studies done by Conard et al. [46] using B3LYP, 6-31G (d,p) basis and methanol (PCM) as solvent the difference was negligible of about 1% with the calculated absorption peak at 381nm. Moreover, the theoretical studies done to resveratrol, also using the B3LYP function with 6-31G* in vacuum, resulted in absorption peak in 315nm [58]. In our work we obtained the λmax of 324nm with a difference of 2,8% to previous work and we attribute this difference to the distinct basis function as well as the solvent employed.

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript chemistry-2085532 entitled " Molecular modeling based on time-dependent density functional theory (TD-DFT) applied to UV-Vis spectrum of natural compounds" describes relevant information about the in silico predictive power of natural molecules with potential to be considered photo protector adjuvants. Overall, the manuscript has been presented well. Authors used sound experimental protocols, good quality data and paper is informative and readable. It could be much more interesting if authors include additional structural information (available on Cambridge Crystallographic Data Centre) to 3-O-methylquercetin, gallic acid, aloin, catechin, quercetin and resveratrol. I recommend the paper for publication after this revision.

1. There are some grammatical errors found in this paper. Also, it would be of great value for readers to use ALL the abbreviations properly.

2. Please, revise the caption of Figure 3 (including “UV-Vis spectra”).  Also, revise the Figure 2: consider that message trumps beauty. 

3. In the “Results and discussion”, the authors may group some of paragraphs (e.g. lines 163-182; 204-221; etc).

4. The authors should highlight the effect of 6-311+G(d,p) base on UV-Vis absorption profiles (and photoprotective compounds).

Author Response

Comments and Suggestions for Authors

The manuscript chemistry-2085532 entitled " Molecular modeling based on time-dependent density functional theory (TD-DFT) applied to UV-Vis spectrum of natural compounds" describes relevant information about the in silico predictive power of natural molecules with potential to be considered photo protector adjuvants. Overall, the manuscript has been presented well. Authors used sound experimental protocols, good quality data and paper is informative and readable. It could be much more interesting if authors include additional structural information (available on Cambridge Crystallographic Data Centre) to 3-O-methylquercetin, gallic acid, aloin, catechin, quercetin and resveratrol. I recommend the paper for publication after this revision.

We appreciate the reviewer's review and comments. As for the use of crystallographic data of chemical structures, we agree that they are extremely important data for the characterization and determination of some molecular properties. However, in the case of this study, the calculations were performed in solvent, methanol, which suggests interference in the minimum energy conformation.

1. There are some grammatical errors found in this paper. Also, it would be of great value for readers to use ALL the abbreviations properly.

Thank you for your thorough reading. The text was reviewed for language and grammar and abbreviations checked.

2. Please, revise the caption of Figure 3 (including “UV-Vis spectra”).  Also, revise the Figure 2: consider that message trumps beauty. 

The captions were reviewed. In the figure 2, we improved the information and captions to be clearer for readers:

Figure 3: Theoretical UV-Vis spectrum of ethylhexyl methoxynnamete, using the TD-DFT methodology with functional B3LYP and base 6-311+G(d,p) and methanol (IEFPCM) as solvent. Blue lines demonstrate the main electronic transitions (singlets).

Figure 2: Computational protocol used to calculate UV-VIS spectra and electronic properties of compounds in Table 1. In the first step, the conformational analysis of the compounds was carried out using the Spartan'14 software and the semi-empirical method PM6, seeking the lowest energy conformation. In the second step, the most stable compound was analyzed in the Gaussian 09 software using the functional B3LYP and base 6-311+G(d,p) and IEFCM methanol as solvent. Next, in the third step, the vibrational analysis (frequency) was carried out with the same theoretical level. Finally, in the fourth step, TD-DFT calculations were performed to calculate the energetic transitions and the theoretical UV-Vis spectra.

3. In the “Results and discussion”, the authors may group some of paragraphs (e.g. lines 163-182; 204-221; etc).

The suggested change has been incorporated in the manuscript.

4. The authors should highlight the effect of 6-311+G(d,p) base on UV-Vis absorption profiles (and photoprotective compounds).

For the DFT methods, functional B3LYP and base 6-311+G(d,p) were used, using the implicit solvent methanol (IEFPCM) in Gaussian 09, the functional B3LYP was used because it is a functional already consolidated in the prediction of UV- Vis. Previous studies by the group, by Garcia 2015, also evaluated the effect of different functionals on theoretical UV-vis predictions and the one that had the highest accuracy for organic molecules with photoprotective qualities was B3LYP [14], [15], [39], [41], [46], [47]. In addition to maintaining the use of a validated methodology for the simulation of UV-vis spectra for molecules with photoprotective characteristics, diffusion (+) and polarization (d,p) functions were added. This generates more accurate and reliable data in studies of electronic distribution for conjugated systems [48].

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The revised manuscript generally answered the questions/comments I raised.