Thymine oxetanes as charge traps for chemical monitoring of nucleic acid mediated transfer of excess electrons.
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Electrons↗
Biomedical subjects
Ulf Diederichsen
Publications and source records attributed to Ulf Diederichsen.
(6-4)-photolyase activity requires a charge shift reaction.
A model compound containing a thymine oxetane moiety linked to a flavin chromophore was investigated regarding (6-4)-photolyase activity. The need for a charge shift reaction was demonstrated by a detailed pH-dependent kinetic analysis.
Catalysis↗
Three-dimensional organization of helices: design principles for nucleobase-functionalized beta-peptides.
The construction and molecular recognition of various three-dimensional biomimetic structures is based on the predictable de novo design of artificial molecules. In this regard beta-peptides are especially interesting, since stable secondary structures are obtained already with short sequences; one of them is the 14-helix in which every third residue has the same orientation. The covalent functionalization of every third 14-helix side chain with nucleobases was used for a reversible organization of two helices based on nucleobase pairing. A series of beta-peptides with various nucleobase sequences was synthesized and the stability of double strand formation was investigated. As few as four nucleobases are sufficient for considerable duplex stability. The stability of base pairing was examined by temperature-dependent UV spectroscopy and the formation of the 14-helix was confirmed by circular dichroism (CD) spectroscopy. The preferred strand orientation of complementary-nucleobase-modified beta-peptide helices was investigated as well as the influence of helix content on the duplex stability. The preorganization of a 14-helix in regard to double-strand recognition was tuned by the sequential order of polar beta-amino acids or by the amount of 2-aminocyclohexanecarboxylic acid units incorporated, which are known to facilitate 14-helix formation, respectively.
Base Pairing↗
Side chain homologation of alanyl peptide nucleic acids: pairing selectivity and stacking.
Alanyl peptide nucleic acids (alanyl-PNAs) are oligomers based on a regular peptide backbone with alternating configuration of the amino acids. All side chains are modified by covalently linked nucleobases. Alanyl-PNAs form very rigid, well defined, and linear double strands based on hydrogen bonding of complementary strands, stacking, and solvation. Side chain homology was examined by comparing a methylene linker (alanyl-PNA) with an ethylene linker (homoalanyl-PNA), a trimethylene linker (norvalyl-PNA), and PNA sequences with mixed linker length between nucleobase and backbone. Side chain homology in combination with a linear double strand topology turned out to be valuable in order to selectively manipulate pairing selectivity (pairing mode) and base pair stacking.
Base Pairing↗
Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II.
MCoTI-I and MCoTI-II from the seeds of Momordica cochinchinensis are inhibitors of trypsin-like proteases and the only known members of the large family of squash inhibitors that are cyclic and contain an additional loop connecting the amino- and the carboxy-terminus. To investigate the contribution of macrocycle formation to biological activity, we synthesized a set of open-chain variants of MCoTI-II that lack the cyclization loop and contain various natural and non-natural amino acid substitutions in the reactive-site loop. Upon replacement of P1 lysine residue #10 within the open-chain variant of MCoTI-II by the non-natural isosteric nucleo amino acid AlaG [beta-(guanin-9-yl)-L-alanine], a conformationally restricted arginine mimetic, residual inhibitory activity was detected, albeit reduced by four orders of magnitude. While the cyclic inhibitors MCoTI-I and MCoTI-II were found to be very potent trypsin inhibitors, with picomolar inhibition constants, the open-chain variants displayed an approximately 10-fold lower affinity. These data suggest that the formation of a circular backbone in the MCoTI squash inhibitors results in enhanced affinity and therefore is a determinant of biological activity.
Alanine↗
Solution and structure of an alternating D,L-peptide.
The crystal structure of H-(L-Tyr-D-Tyr)(4)-L-Lys-OH has been determined to 1.3 A resolution. The D,L-alternating peptide crystallizes in the tetragonal system, space group P4(3)2(1)2, with unit-cell parameters a = b = 27.99 (3), c = 78.93 (8) A. The crystals contain two molecules in the asymmetric unit that form a double-stranded right-handed antiparallel beta-helix. The structure has been solved by SIRAS using a crystal soaked in an iodide-containing solution for 1 min. The programs SHELXD and SHELXE were used to determine the iodide substructure and also the experimental electron-density map. Using the coordinates of known D,L-peptides deposited in the PDB, several attempts were made to solve the structure by molecular-replacement techniques. Although the backbone of the MR model selected shows great similarity and was used to trace the actual peptide structure in the map, it was not possible to obtain the correct solution before the experimental phases became available. The correct fragment orientations are easily determined, but the same does not apply to the translation search. Nevertheless, insights into fragment search and expansion were gained from the tests described in this paper. The correlation coefficient calculated with the resolution shell of data around 2.4 A, a distance corresponding to most 1-3 interatomic vectors, is a particularly good discriminator of correct orientations in the rotation search of small fragments.
Crystallography, X-Ray↗
From IHF protein to design and synthesis of a sequence-specific DNA bending peptide.
The design and synthesis of a small peptide that mimics the integration host factor (IHF), a major nucleoid-associated protein, is reported. IHF induces DNA compaction by sequence-specific binding that leads to significant bending of the DNA double strand. In a modular approach a small L-lysine dendrimer responsible for nonspecific charge-charge interactions was linked to a cyclopeptide. The latter was designed for specific DNA recognition in the minor groove followed by bending of the double strand.
Amino Acid Sequence↗
Solution-phase synthesis of nucleobase-substituted analogues of triostin A.
A synthesis of novel analogues of triostin A presenting two identical or different nucleobases instead of the original quinoxaline substituents has been developed. The DNA bisintercalator triostin A (1) with its rigid backbone provides an optimal scaffold for a parallel preorganization of the intercalating moieties. The bicyclic octadepsipeptide is built up stepwise in solution and modified with various nucleobase-substituted acetic acids at a late stage. The choice of orthogonal protecting groups allows for the synthesis of triostin analogues bearing two different substituents.
DNA↗
Molecular architecture with functionalized beta-peptide helices.
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Circular Dichroism↗