The nucleation of monomeric parallel beta-sheet-like structures and their self-assembly in aqueous solution

The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel beta-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel beta-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel beta-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking alpha-amino acids. The subsequence --hydrophobic residue-1-hydrophobic residue-- is required for folding in the context of a nucleated two-stranded parallel beta-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel beta-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel beta-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar beta-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel beta-sheet structures incorporating N-methylated alpha-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel beta-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel beta-sheet structure

Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance

Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 → Arg + Ser-117 → Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes