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M Reza Ghadiri

Publications and source records attributed to M Reza Ghadiri.

At least 19 recordsLinked to original sources
PubMed2006

Coiled coils at the edge of configurational heterogeneity. Structural analyses of parallel and antiparallel homotetrameric coiled coils reveal configurational sensitivity to a single solvent-exposed amino acid substitution.

A detailed understanding of the mechanisms by which particular amino acid sequences can give rise to more than one folded structure, such as for proteins that undergo large conformational changes or misfolding, is a long-standing objective of protein chemistry. Here, we describe the crystal structures of a single coiled-coil peptide in distinct parallel and antiparallel tetrameric configurations and further describe the parallel or antiparallel crystal structures of several related peptide sequences; the antiparallel tetrameric assemblies represent the first crystal structures of GCN4-derived peptides exhibiting such a configuration. Intriguingly, substitution of a single solvent-exposed residue enabled the parallel coiled-coil tetramer GCN4-pLI to populate the antiparallel configuration, suggesting that the two configurations are close enough in energy for subtle sequence changes to have important structural consequences. We present a structural analysis of the small changes to the helix register and side-chain conformations that accommodate the two configurations and have supplemented these results using solution studies and a molecular dynamics energetic analysis using a replica exchange methodology. Considering the previous examples of structural nonspecificity in coiled-coil peptides, the findings reported here not only emphasize the predisposition of the coiled-coil motif to adopt multiple configurations but also call attention to the associated risk that observed crytstal structures may not represent the only (or even the major) species present in solution.

Amino Acid Sequence↗
PubMed2006

Amino acid dependent formation of phosphate anhydrides in water mediated by carbonyl sulfide.

Carbonyl sulfide (COS), a component of volcanic gas emissions and interstellar gas clouds, is shown to be an efficient condensing agent in the context of phosphate chemistry in aqueous solutions. We report that high-energy aminoacyl-phosphate anhydrides and aminoacyl adenylates are generated in solutions containing amino acids, COS, and the corresponding phosphate molecule. We further show that the mixed anhydrides of amino acids and inorganic phosphate are phosphorylating agents, producing pyrophosphate in better than 30% yield in the presence of Ca2+ precipitates. The amino acid dependent activations of phosphate reported here, which occur in parallel with the production of peptides, suggest that these two reactions may have shared a common intermediate on the prebiotic Earth.

Amino Acids↗
PubMed2005

Discovery of a biologically active thiostrepton fragment.

Design, synthesis, and biological evaluation of several domains of the thiopeptide antibiotic thiostrepton led to the discovery of a biologically active fragment. The biological properties of this novel small organic molecule include antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) bacterial strains, as well as cytotoxic action against a number of cancer cell lines.

Animals↗
PubMed2005

Efficient route to C2 symmetric heterocyclic backbone modified cyclic peptides.

[reaction: see text] A tandem dimerization-macrocyclization approach using 1,3-dipolar azide-alkyne cycloaddition reactions has been employed in the facile and convergent solution phase syntheses of C2 symmetric cyclic peptide scaffolds bearing triazole epsilon2-amino acids as dipeptide surrogates.

Heterocyclic Compounds↗
PubMed2005

Antiviral cyclic D,L-alpha-peptides: targeting a general biochemical pathway in virus infections.

Diverse virus families have evolved to exploit the acidification of endosomal compartments to gain entry into cells. We describe a supramolecular approach for selectively targeting and inhibiting viral infections through this central biochemical pathway. Using adenovirus as a model non-enveloped virus, we have determined that an eight-residue cyclic D,L-alpha-peptide, selected from a directed combinatorial library, can specifically prevent the development of low pH in endocytic vesicles, arrest the escape of virions from the endosome, and abrogate adenovirus infection without an apparent adverse effect on cell viability. The likely generality of this approach against other pH-dependent viral infections is supported by the inhibition of type-A influenza virus escape from endosomes in the presence of the same peptide. Our studies suggest that self-assembling cyclic D,L-alpha-peptides hold considerable potential as a new rational supramolecular approach toward the design and discovery of broad-spectrum antiviral agents.

Amino Acid Sequence↗
PubMed2005

Structure-based engineering of internal cavities in coiled-coil peptides.

Cavities and clefts are frequently important sites of interaction between natural enzymes or receptors and their corresponding substrate or ligand molecules and exemplify the types of molecular surfaces that would facilitate engineering of artificial catalysts and receptors. Even so, structural characterizations of designed cavities are rare. To address this issue, we performed a systematic study of the structural effects of single-amino acid substitutions within the hydrophobic cores of tetrameric coiled-coil peptides. Peptides containing single glycine, serine, alanine, or threonine amino acid substitutions at the buried L9, L16, L23, and I26 hydrophobic core positions of a GCN4-based sequence were synthesized and studied by solution-phase and crystallographic techniques. All peptides adopt the expected tetrameric state and contain tunnels or internal cavities ranging in size from 80 to 370 A(3). Two closely related sequences containing an L16G substitution, one of which adopts an antiparallel configuration and one of which adopts a parallel configuration, illustrate that cavities of different volumes and shapes can be engineered from identical core substitutions. Finally, we demonstrate that two of the peptides (L9G and L9A) bind the small molecule iodobenzene when present during crystallization, leaving the general peptide quaternary structure intact but altering the local peptide conformation and certain superhelical parameters. These high-resolution descriptions of varied molecular surfaces within solvent-occluded internal cavities illustrate the breadth of design space available in even closely related peptides and offer valuable models for the engineering of de novo helical proteins.

Amino Acid Sequence↗
PubMed2005

Modulating charge transfer through cyclic D,L-alpha-peptide self-assembly.

We describe a concise, solid support-based synthetic method for the preparation of cyclic d,l-alpha-peptides bearing 1,4,5,8-naphthalenetetracarboxylic acid diimide (NDI) side chains. Studies of the structural and photoluminescence properties of these molecules in solution show that the hydrogen bond-directed self-assembly of the cyclic d,l-alpha-peptide backbone promotes intermolecular NDI excimer formation. The efficiency of NDI charge transfer in the resulting supramolecular assemblies is shown to depend on the length of the linker between the NDI and the peptide backbone, the distal NDI substituent, and the number of NDIs incorporated in a given structure. The design rationale and synthetic strategies described here should provide a basic blueprint for a series of self-assembling cyclic d,l-alpha-peptide nanotubes with interesting optical and electronic properties.

Molecular Structure↗
PubMed2005

Systemic antibacterial activity of novel synthetic cyclic peptides.

Cyclic peptides with an even number of alternating d,l-alpha-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 microg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-alpha-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

Animals↗
PubMed2004

Heterocyclic peptide backbone modifications in an alpha-helical coiled coil.

In this paper, we present 1,2,3-triazole epsilon2-amino acids incorporated as a dipeptide surrogate at three positions in the sequence of a known alpha-helical coiled coil. Biophysical characterization indicates that the modified peptides retain much of the helical structure of the parent sequence, and that the thermodynamic stability of the coiled coil depends on the position of the incorporation of the epsilon-residue. Crystal structures obtained for each peptide give insight into the chemical behavior and conformational preferences of the non-natural amino acid and show that the triazole ring can participate in the backbone hydrogen bonding of the alpha-helix as well as template an interhelical crossing between chains in the bundle.

Amino Acid Sequence↗
PubMed2004

Carbonyl sulfide-mediated prebiotic formation of peptides.

Almost all discussions of prebiotic chemistry assume that amino acids, nucleotides, and possibly other monomers were first formed on the Earth or brought to it in comets and meteorites, and then condensed nonenzymatically to form oligomeric products. However, attempts to demonstrate plausibly prebiotic polymerization reactions have met with limited success. We show that carbonyl sulfide (COS), a simple volcanic gas, brings about the formation of peptides from amino acids under mild conditions in aqueous solution. Depending on the reaction conditions and additives used, exposure of alpha-amino acids to COS generates peptides in yields of up to 80% in minutes to hours at room temperature.

Amino Acids↗
PubMed2004

Boolean logic functions of a synthetic peptide network.

Living cells can process rapidly and simultaneously multiple extracellular input signals through the complex networks of evolutionary selected biomolecular interactions and chemical transformations. Recent approaches to molecular computation have increasingly sought to mimic or exploit various aspects of biology. A number of studies have adapted nucleic acids and proteins to the design of molecular logic gates and computational systems, while other works have affected computation in living cells via biochemical pathway engineering. Here we report that de novo designed synthetic peptide networks can also mimic some of the basic logic functions of the more complex biological networks. We show that segments of a small network whose graph structure is composed of five nodes and 15 directed edges can express OR, NOR, and NOTIF logic.

Amino Acid Sequence↗
PubMed2004

Design of a directed molecular network.

An ability to rationally design complex networks from the bottom up can offer valuable quantitative model systems for use in gaining a deeper appreciation for the principles governing the self-organization and functional characteristics of complex systems. We report herein the de novo design, graph prediction, experimental analysis, and characterization of simple self-organized, nonlinear molecular networks. Our approach makes use of the sequence-dependent auto- and cross-catalytic functional characteristics of template-directed peptide fragment condensation reactions in neutral aqueous solutions. Starting with an array of 81 sequence similar 32-residue coiled-coil peptides, we estimated the relative stability difference between all plausible A(2)B-type coiled-coil ensembles and used this information to predict the auto- and cross-catalysis pathways and the resulting plausible network motif and connectivities. Similar to most complex systems, the generated graph displays clustered nodes with an overall hierarchical architecture. To test the validity of the design principles used, nine nodes composing a main segment of the graph were experimentally analyzed for their capacity in establishing the predicted network connectivity. The resulting self-organized chemical network is shown to display 25 directed edges in good agreement with the graph analysis estimations. Moreover, we show that by varying the system parameters (presence or absence of certain substrates or templates), its operating network motif can be altered, even to the extremes of turning pathways on or off. We suggest that this approach can be expanded for the construction of large-scale networks, offering a means to study and to understand better the emergent, collective behaviors of networks.

Amino Acid Sequence↗
PubMed2003

A heterocyclic peptide nanotube.

An open-ended hollow tubular structure is designed based on hydrogen-bond-directed self-assembly of a chimeric cyclic peptide subunit comprised of alternating alpha- and epsilon-amino acids. The design features a novel 1,4-disubstituted-1,2,3-triazole epsilon-amino acid and its utility as a peptide backbone substitute. The N-Fmoc-protected epsilon-amino acid was synthesized in high yield and optical purity in three steps from readily available starting materials and was employed in solid-phase peptide synthesis to afford the desired cyclic peptide structure. The cyclic peptide self-assembly has been studied in solution by (1)H NMR and mass spectrometry and the resulting tubular ensemble characterized in the solid state by X-ray crystallography.

Amino Acids↗
PubMed2003

DNA detection and signal amplification via an engineered allosteric enzyme.

Rapid, sensitive, and sequence-specific DNA detection can be achieved in one step using an engineered intrasterically regulated enzyme. The semi-synthetic inhibitor-DNA-enzyme (IDE) construct (left) rests in the inactive state but upon exposure to a complementary DNA sequence undergoes a DNA hybridization-triggered allosteric enzyme activation (right). The ensuing rapid substrate turnover provides the built-in signal amplification mechanism for detecting approximately 10 fmol DNA in less than 3 min under physiological conditions.

Bacillus cereus↗
PubMed2003

DNA-based photonic logic gates: AND, NAND, and INHIBIT.

Conventional microprocessors use elementary logic gates to perform complex computational tasks. Mimicking such computational processes using purely molecular systems has been limited in most cases by the lack of design generality or potential addressability of existing molecular logic gates. Herein we report that by employing the universal recognition properties of DNA simple photonic logic gates can be created that are capable of AND, NAND, and INHIBIT logic operations.

Computational Biology↗