How does a knotted protein fold?

The issue of how a newly synthesized polypeptide chain folds to form a protein with a unique three-dimensional structure, otherwise known as the 'protein-folding problem', remains a fundamental question in the life sciences. Over the last few decades, much information has been gathered about the mechanisms by which proteins fold. However, despite the vast topological diversity observed in biological structures, it was thought improbable, if not impossible, that a polypeptide chain could 'knot' itself to form a functional protein.

Is the Induction Energy Important for Modeling Organic Crystals?

We compare two methods for estimating the induction energy in organic molecular crystals by approximating the charge density polarization in the crystalline state. The first is a distributed atomic polarizability model combined with distributed multipole moments, derived from ab initio monomer properties. The second uses an ab initio calculation of the molecular charge density in a point-charge field.

High Catalytic Activity of Chiral Amino Alcohol Ligands Anchored to Polystyrene Resins.

Enantiomerically pure (2S,3S)-2,3-epoxy-3-phenylpropanol (3) has been anchored to Merrifield resins with different degrees of cross-linking and functionalization. The resulting epoxy-functionalized resins 4 have been submitted to completely regioselective (C-3 attack) and stereospecific ring-opening with secondary amines [piperidine (a), N-methylpiperazine (b), and cis-2,6-dimethylpiperidine (c)] in the presence of lithium perchlorate to afford (2R,3R)-3-(dialkylamino)-2-hydroxy-3-phenylpropoxy resin ethers 5a-c. The progress of these two processes has been monitored by (13)C gel-phase NMR spectroscopy.

Molecular basis of Celmer's rules: role of the ketosynthase domain in epimerisation and demonstration that ketoreductase domains can have altered product specificity with unnatural substrates.

Background: Polyketides are structurally diverse natural products with a range of medically useful activities. Non-aromatic bacterial polyketides are synthesised on modular polyketide synthase multienzymes (PKSs) in which each cycle of chain extension requires a different 'module' of enzymatic activities. Attempts to design and construct modular PKSs that synthesise specified novel polyketides provide a particularly stringent test of our understanding of PKS structure and function.

Role of type II thioesterases: evidence for removal of short acyl chains produced by aberrant decarboxylation of chain extender units.

Background: Modular polyketide synthases (PKSs) function as molecular assembly lines in which polyketide chains are assembled by successive addition of chain extension units. At the end of the assembly line, there is usually a covalently linked type I thioesterase domain (TE I), which is responsible for release of the completed acyl chain from its covalent link to the synthase. Additionally, some PKS clusters contain a second thioesterase gene (TE II) for which there is no established role.

Structural characterization of a mutant peptide derived from ubiquitin: implications for protein folding.

The formation of the N-terminal beta-hairpin of ubiquitin is thought to be an early event in the folding of this small protein. Previously, we have shown that a peptide corresponding to residues 1-17 of ubiquitin folds autonomously and is likely to have a native-like hairpin register. To investigate the causes of the stability of this fold, we have made mutations in the amino acids at the apex of the turn.

Autonomous folding of a peptide corresponding to the N-terminal beta-hairpin from ubiquitin.

The N-terminal 17 residues of ubiquitin have been shown by 1H NMR to fold autonomously into a beta-hairpin structure in aqueous solution. This structure has a specific, native-like register, though side-chain contacts differ in detail from those observed in the intact protein. An autonomously folding hairpin has previously been identified in the case of streptococcal protein G, which is structurally homologous with ubiquitin, but remarkably, the two are not in topologically equivalent positions in the fold.

Nucleoside analogs. 14. The synthesis of antitumor activity in mice of molecular combinations of 5-fluorouracil and N-(2-Chloroethyl)-N-nitrosourea moieties separated by a three-carbon chain.

5-fluorouracil (5-FU) seco-nucleosdies having as the "sugar" moiety a two-carbon (C2) side chain carrying a N-(2-chloroethyl)-N-nitrosourea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast enough for significant contribution to the high activity they showed against colon and breast tumors in mice. In the present study of the synthesis of the more reactive C3 seco-nucleosides, it emerged that, of various groups attached to the aldehydic center in the precursor phthalimides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relatively large amounts of reagent methanethiol, and exploration of alternatives involving alpha-chlorination of alkyl methyl sulfide or Pummerer rearrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields.