Christian Lehmann

Crystal structure of a synthetic cyclodecapeptide for template-assembled synthetic protein design

The structural prototype of a new generation of regioselectively addressable functionalized templates (RAFTs) for use in protein de novo design has been synthesized and crystallized. The structure of the aromatically substituted cyclodecapeptide was determined by X‐ray diffraction; it consists of an antiparallel β sheet spanned by heterochirally induced type II′ β turns, similar to that observed in gramicidin S. The three‐dimensional structure of the artificial template was also examined by an NMR spectroscopic analysis in solution and shown to be compatible with a β‐sheet plane suitable for accommodating secondary functional peptide fragments for the synthesis of template‐assembled synthetic proteins (TASPs).

Bicyclo[3.2.1]amide-DNA: a chiral, nonchiroselective base-pairing system

The design, synthesis, and base-pairing properties of bicyclo[3.2.1]amide-DNA (bca-DNA), a novel phosphodiester-based DNA analogue, are reported. This analogue consists of a conformationally constrained backbone entity, which emulates a B-DNA geometry, to which the nucleo-bases were attached through an extended, acyclic amide linker. Homobasic adenine-containing bca decamers form duplexes with complementary oligonucleotides containing bca, DNA, RNA, and, surprisingly, also L-RNA backbones. UV and CD spectroscopic investigations revealed the duplexes with D- or L-complements to be of similar stability and enantiomorphic in structure. Bca oligonucleotides that contain all four bases form strictly antiparallel, left-handed complementary duplexes with themselves and with complementary DNA, but not with RNA. Base-mismatch discrimination is comparable to that of DNA, while the overall thermal stabilities of bca-oligonucleotide duplexes are inferior to those of DNA or RNA. A detailed molecular modeling study of left- and right-handed bca-DNA-containing duplexes showed only minor changes in the backbone structure and revealed a structural switch around the base-linker unit to be responsible for the generation of enantiomorphic duplex structures. The obtained data are discussed with respect to the structural and energetic role of the ribofuranose entities in DNA and RNA association.

Stereocontrol during the formation of 2-C mono-arylated pseudo-prolines by aromatic stacking interaction

When treated with anisaldehyde dimethylacetal the O-benzyl ester protected dipeptide Fmoc-NMeIle-Thr-OBzl (2, cf. Scheme 3), cyclizes to the 2-C(S) epimer 3b assigned by NMR spectroscopy to chirality (R) at the 2-C position of the resulting substituted 1,3-oxazolidine (Psi Pro) unit, while in the acetalization of the corresponding O-methylester Fmoc-NMeIle-Thr-OMe (6),the 2-C(S) epimer 7a is predominantly formed stereoselectively and in quantitative yield. The course of the reaction can be rationalized by aromatic stacking interactions involving the benzyl ester and aryl ether groups in a transition state close to a product structure of(R) chirality, whereas the lack of such interactions in the case of the methyl ester can be used to direct the acetalization towards the 2-C(S) epimer

Engineering of zinc finger and MHC motifs to locked-in tertiary folds

The assembly of helical and β-sheet peptide blocks containing reactive chain ends results inhighly branched chain architectures (‘locked-in folds’) mimicking native tertiary structures.This molecular kit strategy allows to bypass the protein folding problem in protein de novodesign and gives access to protein mimetics of high thermodynamic stability. The validity ofthis concept is exemplified for the design and synthesis of locked-in folds mimicking the zincfinger and MHC folding motifs.

Template assembled synthetic peptides (TASP) as receptor mimetics and ‘locked-in’ tertiary folds

A symposium report. A new concept for the construction of protein mimetics based on the sepn. of functional and structural domains in proteins has been evaluated by the successful design and total synthesis of two prototype TASP mols. [on SciFinder (R)]

Molecular Modeling: Indispensable Tool at the Interface Between Structural Analysis and Molecular Design

As exemplified by last centuries milestone rationalization of particular peptidic and nucleic acid biomolecular fibre diffraction patterns through their helical conformation models [1], the interpretation of structural data has always stood at the onset of any molecular modeling endeavor. Ever since structural information encompassing low molecular weight peptides [2] as well as macromolecular protein structures [3] has been rapidly growing, computer-assisted tools for structure analysis, comparison and design will become more and more important. The present communication features results obtained with a recently introduced software suite [4] based on a united atom force field approach originally developed for structure modeling in medicinal chemistry [5].

A base-labile protecting group (fluorenylmethoxycarbonyl) for the 5'-hydroxy function of nucleosides.

Many popular synthesis strategies look for appropriate 2′‐O‐protection methods to use in conjunction with 5′‐O‐trityl chemistry. In contrast, this unit describes the use of FMOC as a 5′‐protecting group in conjunction with a ketal‐type 2′‐O‐protecting group, 4‐methoxytetrahydropyran‐4‐yl (MTHP). The synthesis of all four 2′‐O‐MTHP‐5′‐O‐FMOC‐protected ribonucleosides and 5′‐O‐FMOC‐2′‐deoxythymidine is described, as is the preparation of the N‐protected, 2′‐O‐MTHP‐protected starting nucleosides.