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Computational chemistry studies of UV induced processes in human skin
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

This thesis presents and uses the techniques of computational chemistry to explore two different processes induced in human skin by ultraviolet light. The first is the transformation of urocanic acid into a immunosuppressing agent, and the other is the enzymatic action of the 8-oxoguanine glycosylase enzyme.

The photochemistry of urocanic acid is investigated by time-dependent density functional theory. Vertical absorption spectra of the molecule in different forms and environments is assigned and candidate states for the photochemistry at different wavelengths are identified.

Molecular dynamics simulations of urocanic acid in gas phase and aqueous solution reveals considerable flexibility under experimental conditions, particularly for for the cis isomer where competition between intra- and inter-molecular interactions increases flexibility.

A model to explain the observed gas phase photochemistry of urocanic acid is developed and it is shown that a reinterpretation in terms of a mixture between isomers significantly enhances the agreement between theory and experiment , and resolves several peculiarities in the spectrum.

A model for the photochemistry in the aqueous phase of urocanic acid is then developed, in which two excited states governs the efficiency of photoisomerization. The point of entrance into a conical intersection seam is shown to explain the wavelength dependence of photoisomerization quantum yield.

Finally some mechanistic aspects of the DNA repair enzyme 8-oxoguanine glycosylase is investigated with density functional theory. It is found that the critical amino acid of the active site can provide catalytic power in several different manners, and that a recent proposal involving a SN1 type of mechanism seems the most efficient one.

sted, utgiver, år, opplag, sider
Stockholm: Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi , 2004. , s. 260
Emneord [en]
Photochemistry, Theoretical chemistry, Density functional theory, UV effects, TD-DFT, enzyme catalysis, DNA damage, Molecular dynamics
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-261ISBN: 91-7265-960-2 (tryckt)OAI: oai:DiVA.org:su-261DiVA, id: diva2:191668
Disputas
2004-10-29, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Veileder
Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07bibliografisk kontrollert
Delarbeid
1. A TD-DFT study of the photochemistry of urocanic acid in biologically relevant forms and solvent - influence of ionic, rotameric and protomeric state
Åpne denne publikasjonen i ny fane eller vindu >>A TD-DFT study of the photochemistry of urocanic acid in biologically relevant forms and solvent - influence of ionic, rotameric and protomeric state
2001 Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 123, nr 40, s. 9817-Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-23380 (URN)
Merknad
Part of urn:nbn:se:su:diva-261Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07bibliografisk kontrollert
2. Hydration structure and conformational dynamics of urocanic acid: a computer simulation study
Åpne denne publikasjonen i ny fane eller vindu >>Hydration structure and conformational dynamics of urocanic acid: a computer simulation study
2002 Inngår i: Molecular Physics, ISSN 0026-8976, Vol. 100, nr 12, s. 1873-Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-23381 (URN)
Merknad
Part of urn:nbn:se:su:diva-261Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07bibliografisk kontrollert
3. Gas phase photoisomerization of urocanic acid - a theoretical study
Åpne denne publikasjonen i ny fane eller vindu >>Gas phase photoisomerization of urocanic acid - a theoretical study
2003 Inngår i: Chemical Physics Letters, ISSN 0009-2614, Vol. 370, nr 5-6, s. 625-Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-23382 (URN)
Merknad
Part of urn:nbn:se:su:diva-261Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07bibliografisk kontrollert
4. A theoretical study of the photoisomerization of anionic urocanic acid
Åpne denne publikasjonen i ny fane eller vindu >>A theoretical study of the photoisomerization of anionic urocanic acid
Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:su:diva-23383 (URN)
Merknad
Part of urn:nbn:se:su:diva-261Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07bibliografisk kontrollert
5. Theoretical study of the human DNA repair protein hOGG1 activity
Åpne denne publikasjonen i ny fane eller vindu >>Theoretical study of the human DNA repair protein hOGG1 activity
2005 (engelsk)Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 109, nr 8, s. 1713-1719Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We have examined the role of the catalytic lysine (Lys 249) in breaking the glycosidic bond of 8-oxoguanine in the enzyme human 8-oxoguanine DNA glycosylase. Until quite recently it has been assumed that this lysine acts as a nucleophile in an SN2 type of reaction after being activated through a donation of a proton to a strictly conserved aspartate, also located in the active site. However, evidence from crystallographic, as well as biochemical studies, questions this assumption mainly because the lysine is not ideally positioned for such an attack. In addition, the catalytic activity is preserved even after that aspartate is mutated to a residue not accepting protons, but still keeping the interactions in the active site. In this study, we have investigated several different reaction mechanisms to discover plausible ways where the lysine could assist in breaking the glycosidic bond. We use hybrid density functional theory to characterize both associative and dissociative pathways. We find that the smallest energetical barrier involves an SN1 type of mechanism where the lysine electrostatically stabilizes the dissociating base and then donates a proton with a very small barrier and then finally attacks the sugar ring to create the covalently bound protein−DNA intermediate complex. The SN2 mechanism also has a lower barrier than the “spontaneous” bond breaking but considerably above that of the SN1 reaction. However, in current conditions, the reactants placed in a conformation posed for an SN2 reaction is substantially more stable than if posed for the SN1 reaction, indicating that the active site has to bind stronger to the latter in order to achieve a full catalytic effect. An analysis of the polarization of the transition states shows that the polarization is largest for the SN1 reaction, indicating that this path will gain most by being placed in a prepolarized active site. These findings give further support to the hypothesis that a dissociative mechanism may be the preferred mode of action for this type of enzymes.

sted, utgiver, år, opplag, sider
American Chemical Society, 2005
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-23384 (URN)10.1021/jp045686m (DOI)
Merknad
Part of urn:nbn:se:su:diva-261Tilgjengelig fra: 2004-10-07 Laget: 2004-10-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert

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