D. D. Nguyen, D. D. Nguyen, N. Jones, S. Hoffmann, J. Spanget-Larsen
Anthralin (1,8-dihydroxyanthrone, 1,8-dihydroxy-9(10H)-anthracenone), also known as dithranol and cignolin, is one of the most efficient drugs in the treatment of psoriasis and other skin diseases. The precise mode of biochemical action is not fully understood, but the activity of the drug is increased by the influence of UV radiation. In the present investigation, the UV absorption of anthralin is studied by synchrotron radiation linear dichroism (SRLD) spectroscopy on molecular samples partially aligned in stretched polyethylene, covering the near and vacuum UV regions with wavenumbers ranging from 23,000 to 58,000 cm–1(430–170 nm). The observed polarization spectra are well predicted by quantum chemical calculations using time-dependent density functional theory (TD–DFT). About a dozen spectral features are assigned to computed electronic transitions. The calculations support interpretation of the anomalous fluorescence of anthralin as a result of barrier-less excited state intramolecular proton transfer (ESIPT) to the tautomer 8,9-dihydroxy-1(10H)-anthracenone.
{"title":"UV synchrotron radiation linear dichroism spectroscopy of the anti-psoriatic drug anthralin","authors":"D. D. Nguyen, D. D. Nguyen, N. Jones, S. Hoffmann, J. Spanget-Larsen","doi":"10.7717/peerj-pchem.5","DOIUrl":"https://doi.org/10.7717/peerj-pchem.5","url":null,"abstract":"Anthralin (1,8-dihydroxyanthrone, 1,8-dihydroxy-9(10H)-anthracenone), also known as dithranol and cignolin, is one of the most efficient drugs in the treatment of psoriasis and other skin diseases. The precise mode of biochemical action is not fully understood, but the activity of the drug is increased by the influence of UV radiation. In the present investigation, the UV absorption of anthralin is studied by synchrotron radiation linear dichroism (SRLD) spectroscopy on molecular samples partially aligned in stretched polyethylene, covering the near and vacuum UV regions with wavenumbers ranging from 23,000 to 58,000 cm–1(430–170 nm). The observed polarization spectra are well predicted by quantum chemical calculations using time-dependent density functional theory (TD–DFT). About a dozen spectral features are assigned to computed electronic transitions. The calculations support interpretation of the anomalous fluorescence of anthralin as a result of barrier-less excited state intramolecular proton transfer (ESIPT) to the tautomer 8,9-dihydroxy-1(10H)-anthracenone.","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46854601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Takuya Shimato, K. Kasahara, J. Higo, Takuya Takahashi
The generalized ensemble approach with the molecular dynamics (MD) method has been widely utilized. This approach usually has two features. (i) A bias potential, whose strength is replaced during a simulation, is applied. (ii) Sampling can be performed by many parallel runs of simulations. Although the frequency of the bias-strength replacement and the number of parallel runs can be adjusted, the effects of these settings on the resultant ensemble remain unclear. In this study, we performed multicanonical MD simulations for a foldable mini-protein (Trp-cage) and two unstructured peptides (8- and 20-residue poly-glutamic acids) with various settings. As a result, running many short simulations yielded robust results for the Trp-cage model. Regarding the frequency of the bias-potential replacement, although using a high frequency enhanced the traversals in the potential energy space, it did not promote conformational changes in all the systems.
{"title":"Effects of number of parallel runs and frequency of bias-strength replacement in generalized ensemble molecular dynamics simulations","authors":"Takuya Shimato, K. Kasahara, J. Higo, Takuya Takahashi","doi":"10.7717/peerj-pchem.4","DOIUrl":"https://doi.org/10.7717/peerj-pchem.4","url":null,"abstract":"\u0000\u0000The generalized ensemble approach with the molecular dynamics (MD) method has been widely utilized. This approach usually has two features. (i) A bias potential, whose strength is replaced during a simulation, is applied. (ii) Sampling can be performed by many parallel runs of simulations. Although the frequency of the bias-strength replacement and the number of parallel runs can be adjusted, the effects of these settings on the resultant ensemble remain unclear.\u0000\u0000\u0000\u0000In this study, we performed multicanonical MD simulations for a foldable mini-protein (Trp-cage) and two unstructured peptides (8- and 20-residue poly-glutamic acids) with various settings.\u0000\u0000\u0000\u0000As a result, running many short simulations yielded robust results for the Trp-cage model. Regarding the frequency of the bias-potential replacement, although using a high frequency enhanced the traversals in the potential energy space, it did not promote conformational changes in all the systems.\u0000","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45369190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The liquid-vacuum interface of molten alkali carbonate salts is studied with molecular dynamics simulations. Three salts comprised of LixNayKzCO3 near their respective eutectic concentrations are considered to understand the distribution of ions relative to a liquid-vacuum interface and their diffusivity. These simulations show that each of the cations accumulate at the interface preferentially compared to carbonate. The cation ordering is found to inversely correspond to cation radius, with K being the most likely occupant at the surface, followed by Na, Li, and then the anion. Similar to other studies, the carbonate is found to diffuse more slowly than the cations, but we do observe small differences in diffusion between compositions that present opportunities to optimize ion transport. These results hold consequences for our understanding of ion behavior in molten carbonate salts and the performance of devices employ these electrolytes.
{"title":"Structure and diffusion of molten alkali carbonate salts at the liquid-vacuum interface","authors":"G. Lindberg","doi":"10.7717/peerj-pchem.3","DOIUrl":"https://doi.org/10.7717/peerj-pchem.3","url":null,"abstract":"The liquid-vacuum interface of molten alkali carbonate salts is studied with molecular dynamics simulations. Three salts comprised of LixNayKzCO3 near their respective eutectic concentrations are considered to understand the distribution of ions relative to a liquid-vacuum interface and their diffusivity. These simulations show that each of the cations accumulate at the interface preferentially compared to carbonate. The cation ordering is found to inversely correspond to cation radius, with K being the most likely occupant at the surface, followed by Na, Li, and then the anion. Similar to other studies, the carbonate is found to diffuse more slowly than the cations, but we do observe small differences in diffusion between compositions that present opportunities to optimize ion transport. These results hold consequences for our understanding of ion behavior in molten carbonate salts and the performance of devices employ these electrolytes.","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46557527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osvaldo A Martin, Yury Vorobjev, Harold A Scheraga, Jorge A Vila
There is abundant theoretical evidence indicating that a mirror image of Protein A may occur during the protein folding process. However, as to whether such mirror image exists in solution is an unsolved issue. Here we provide outline of an experimental design aimed to detect the mirror image of Protein A in solution. The proposal is based on computational simulations indicating that the use of a mutant of protein A, namely Q10H, could be used to detect the mirror image conformation in solution. Our results indicate that the native conformation of the protein A should have a pKa, for the Q10H mutant, at ≈6.2, while the mirror-image conformation should have a pKa close to ≈7.3. Naturally, if all the population is in the native state for the Q10H mutant, the pKa should be ≈6.2, while, if all are in the mirror-image state, it would be ≈7.3, and, if it is a mixture, the pKa should be largerthan 6.2, presumably in proportion to the mirror population. In addition, evidence is provided indicating the tautomeric distribution of H10 must also change between the native and mirror conformations. Although this may not be completely relevant for the purpose of determining whether the protein A mirror image exists in solution, it could provide valuable information to validate the pKa findings. We hope this proposal will foster experimental work on this problem either by direct application of our proposed experimental design or serving as inspiration and motivation for other experiments.
{"title":"Outline of an experimental design aimed to detect a protein A mirror image in solution.","authors":"Osvaldo A Martin, Yury Vorobjev, Harold A Scheraga, Jorge A Vila","doi":"10.7717/peerj-pchem.2","DOIUrl":"https://doi.org/10.7717/peerj-pchem.2","url":null,"abstract":"<p><p>There is abundant theoretical evidence indicating that a mirror image of <i>Protein A</i> may occur during the protein folding process. However, as to whether such mirror image exists in solution is an unsolved issue. Here we provide outline of an experimental design aimed to detect the mirror image of <i>Protein A</i> in solution. The proposal is based on computational simulations indicating that the use of a mutant of protein A, namely Q10H, could be used to detect the mirror image conformation in solution. Our results indicate that the native conformation of the protein A should have a pKa, for the Q10H mutant, at ≈6.2, while the mirror-image conformation should have a pKa close to ≈7.3. Naturally, if all the population is in the native state for the Q10H mutant, the pKa should be ≈6.2, while, if all are in the mirror-image state, it would be ≈7.3, and, if it is a mixture, the pKa should be largerthan 6.2, presumably in proportion to the mirror population. In addition, evidence is provided indicating the tautomeric distribution of H10 must also change between the native and mirror conformations. Although this may not be completely relevant for the purpose of determining whether the protein A mirror image exists in solution, it could provide valuable information to validate the pKa findings. We hope this proposal will foster experimental work on this problem either by direct application of our proposed experimental design or serving as inspiration and motivation for other experiments.</p>","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168520/pdf/nihms-1572619.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39071443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effect of the repetition rate of femtosecond laser pulses on the two-photon absorption and nonlinear refraction of pure organic liquids is presented using the conventional Z-scan technique. Such a study provides a way to determine the nature of light-matter interaction, explicitly enabling the identification of the linear versus nonlinear regimes. Based on the type of light-matter interaction, we have identified the thermal load dissipation time for the organic liquids. Our experimental results are in good agreement with the theoretically calculated decay time for the dissipation of thermal load.
{"title":"Effect of femtosecond laser pulse repetition rate on nonlinear optical properties of organic liquids","authors":"S. Maurya, D. Yadav, D. Goswami","doi":"10.7717/peerj-pchem.1","DOIUrl":"https://doi.org/10.7717/peerj-pchem.1","url":null,"abstract":"The effect of the repetition rate of femtosecond laser pulses on the two-photon absorption and nonlinear refraction of pure organic liquids is presented using the conventional Z-scan technique. Such a study provides a way to determine the nature of light-matter interaction, explicitly enabling the identification of the linear versus nonlinear regimes. Based on the type of light-matter interaction, we have identified the thermal load dissipation time for the organic liquids. Our experimental results are in good agreement with the theoretically calculated decay time for the dissipation of thermal load.","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44707141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Léa El Khoury, Krystel El Hage, Jean‐Philip Piquemal, S. Fermandjian, R. Maroun, N. Gresh, Zeina Hobaika
Three integrase strand transfer inhibitors are in intensive clinical use, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). The onset of integrase resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviral nucleobases, which are little, if at all, mutation-prone. We report experimental results of anisotropy fluorescence titrations of viral DNA by these three drugs. These show the DTG > EVG > RAL ranking of their inhibitory activities of the intasome to correspond to that of their free energies of binding, ∆Gs, to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, ∆H, the entropy undergoing marginal variations. We sought whether this ranking might be reproduced through quantum chemistry (QC) Density Functional Theory calculations of intermolecular interaction energies between simplified models consisting of sole halobenzene ring and the highly conserved retroviral nucleobases G4 and C16. These calculations showed that binding of EVG has a small preference over DTG, while RAL ranked third. This indicates that additional interactions of the diketoacid parts of the drugs with DNA could be necessary to further enable preferential binding of DTG. The corresponding ∆Etotvalues computed with a polarizable molecular mechanics/dynamics procedure, Sum of Interactions Between Fragments Ab initio computed (SIBFA), showed good correlations with this ∆E(QC) ranking. These validations are an important step toward the use of polarizable molecular dynamics simulations on DTG or EVG derivatives in their complexes with the complete intasome, an application now motivated and enabled by the advent of currently developed and improved massively parallel software.
{"title":"Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities","authors":"Léa El Khoury, Krystel El Hage, Jean‐Philip Piquemal, S. Fermandjian, R. Maroun, N. Gresh, Zeina Hobaika","doi":"10.7717/PEERJ-PCHEM.6","DOIUrl":"https://doi.org/10.7717/PEERJ-PCHEM.6","url":null,"abstract":"Three integrase strand transfer inhibitors are in intensive clinical use, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). The onset of integrase resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviral nucleobases, which are little, if at all, mutation-prone. We report experimental results of anisotropy fluorescence titrations of viral DNA by these three drugs. These show the DTG > EVG > RAL ranking of their inhibitory activities of the intasome to correspond to that of their free energies of binding, ∆Gs, to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, ∆H, the entropy undergoing marginal variations. We sought whether this ranking might be reproduced through quantum chemistry (QC) Density Functional Theory calculations of intermolecular interaction energies between simplified models consisting of sole halobenzene ring and the highly conserved retroviral nucleobases G4 and C16. These calculations showed that binding of EVG has a small preference over DTG, while RAL ranked third. This indicates that additional interactions of the diketoacid parts of the drugs with DNA could be necessary to further enable preferential binding of DTG. The corresponding ∆Etotvalues computed with a polarizable molecular mechanics/dynamics procedure, Sum of Interactions Between Fragments Ab initio computed (SIBFA), showed good correlations with this ∆E(QC) ranking. These validations are an important step toward the use of polarizable molecular dynamics simulations on DTG or EVG derivatives in their complexes with the complete intasome, an application now motivated and enabled by the advent of currently developed and improved massively parallel software.","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49013093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-04-24DOI: 10.26434/chemrxiv.8003813.v1
Mads Koerstz, Anders S. Christensen, K. Mikkelsen, M. Nielsen, Jan H. Jensen
The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising candidate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e., the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density functional theory to virtually screen over 230 billion substituted DHA molecules to identify promising candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent compound, which should correspond to a half-life of about 10 days—4 months. This is considerably longer than the 3–39 h (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. Our paper makes two main important contributions: (1) a novel and generally applicable methodological approach that makes screening of huge libraries for properties involving chemical reactivity with modest computational resources, and (2) a clear demonstration that the storage capacity of the DHA/VHF thermocouple cannot be increased to >0.5 kJ/g by combining simple substituents.
{"title":"High throughput virtual screening of 230 billion molecular solar heat battery candidates","authors":"Mads Koerstz, Anders S. Christensen, K. Mikkelsen, M. Nielsen, Jan H. Jensen","doi":"10.26434/chemrxiv.8003813.v1","DOIUrl":"https://doi.org/10.26434/chemrxiv.8003813.v1","url":null,"abstract":"The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising candidate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e., the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density functional theory to virtually screen over 230 billion substituted DHA molecules to identify promising candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent compound, which should correspond to a half-life of about 10 days—4 months. This is considerably longer than the 3–39 h (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. Our paper makes two main important contributions: (1) a novel and generally applicable methodological approach that makes screening of huge libraries for properties involving chemical reactivity with modest computational resources, and (2) a clear demonstration that the storage capacity of the DHA/VHF thermocouple cannot be increased to >0.5 kJ/g by combining simple substituents.","PeriodicalId":93220,"journal":{"name":"PeerJ physical chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47440562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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