Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rational design of helical architectures

ABSTRACT: Nature has mastered the art of creating complex structures through self-assembly of simpler building blocks. Adapting such a bottom-up view provides a potential route to the fabrication of novel materials. However, this approach suffers from the lack of a sufficiently detailed understanding of the noncovalent forces that hold the self-assembled structures together. Here we demonstrate that nature can indeed guide us, as we explore routes to helicity with achiral building blocks driven by the interplay between two competing length scales for the interactions, as in DNA. By characterizing global minima for clusters, we illustrate several realizations of helical architecture, the simplest one involving ellipsoids of revolution as building blocks. In particular, we show that axially symmetric soft discoids can self-assemble into helical columnar arrangements. Understanding the molecular origin of such spatial organisation has important implications for the rational design of materials with useful optoelectronic applications.

SUBMITTER: Chakrabarti D

PROVIDER: S-EPMC2787114 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Rational design of α-helical tandem repeat proteins with closed architectures.

Project description:Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials. The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks. The overall architecture of tandem repeat protein structures--which is dictated by the internal geometry and local packing of the repeat building blocks--is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners, to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis. Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed α-solenoid repeat structures (α-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the amino (N) and carboxy (C) termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering, our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed α-solenoid repeats with a left-handed helical architecture that--to our knowledge--is not yet present in the protein structure database.

| S-EPMC4727831 | biostudies-literature

Rational design and application of responsive alpha-helical peptide hydrogels.

Project description:Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs, and as supports for cell growth and tissue engineering. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials. Here, we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely alpha-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of alpha-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks of fibrils melt on heating, whereas those formed through hydrophobic fibril-fibril interactions strengthen when warmed. The hSAFs are dual-peptide systems that gel only on mixing, which gives tight control over assembly. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture.

| S-EPMC2869032 | biostudies-literature

Rational design of a helical peptide inhibitor targeting c-Myb-KIX interaction.

Project description:The transcription factor c-Myb promotes the proliferation of hematopoietic cells by interacting with the KIX domain of CREB-binding protein; however, its aberrant expression causes leukemia. Therefore, inhibitors of the c-Myb-KIX interaction are potentially useful as antitumor drugs. Since the intrinsically disordered transactivation domain (TAD) of c-Myb binds KIX via a conformational selection mechanism where helix formation precedes binding, stabilizing the helical structure of c-Myb TAD is expected to increase the KIX-binding affinity. Here, to develop an inhibitor of the c-Myb-KIX interaction, we designed mutants of the c-Myb TAD peptide fragment where the helical structure is stabilized, based on theoretical predictions using AGADIR. Three of the four initially designed peptides each had a different Lys-to-Arg substitution on the helix surface opposite the KIX-binding interface. Furthermore, the triple mutant with three Lys-to-Arg substitutions, named RRR, showed a high helical propensity and achieved three-fold higher affinity to KIX than the wild-type TAD with a dissociation constant of 80 nM. Moreover, the RRR inhibitor efficiently competed out the c-Myb-KIX interaction. These results suggest that stabilizing the helical structure based on theoretical predictions, especially by conservative Lys-to-Arg substitutions, is a simple and useful strategy for designing helical peptide inhibitors of protein-protein interactions.

| S-EPMC8776815 | biostudies-literature

A minimal length rigid helical peptide motif allows rational design of modular surfactants.

Project description:Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded ?-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.

| S-EPMC5241864 | biostudies-literature

Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

Project description:Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs comprises a short α-helix. In this work, helical oligopeptides mimicking the VEGF-C helix were rationally designed based on structural analyses and computational studies. The helical conformation was stabilized by optimizing intramolecular interactions and by introducing helix-inducing Cα,α-disubstituted amino acids. The conformational features of the synthetic peptides were characterized by circular dichroism and nuclear magnetic resonance, and their receptor binding properties and antiangiogenic activity were determined. The best hits exhibited antiangiogenic activity in vitro at nanomolar concentrations and were resistant to proteolytic degradation.

| S-EPMC6449863 | biostudies-literature

Rational Design of Small Molecules as Vaccine Adjuvants

Project description:Analysis of whole mouse muscle and inguinal lymph node gene expression signature induced after 24h by in-vivo intramuscularly administration of R848, SMIP-7.7, SMIP-7.8 and 4%DMSO controls. Analysis of whole mouse muscle and inguinal lymph node gene expression signature induced after 6h by in-vivo intramuscularly administration of R848 and SMIP-7.2 in 1% DMSO, and SMIP-7.10 and SMIP-7.10+alum in Buffer.

2015-11-02 | E-MTAB-2948 | biostudies-arrayexpress

Classification of ?-helical membrane proteins using predicted helix architectures.

Project description:Despite significant methodological advances in protein structure determination high-resolution structures of membrane proteins are still rare, leaving sequence-based predictions as the only option for exploring the structural variability of membrane proteins at large scale. Here, a new structural classification approach for ?-helical membrane proteins is introduced based on the similarity of predicted helix interaction patterns. Its application to proteins with known 3D structure showed that it is able to reliably detect structurally similar proteins even in the absence of any sequence similarity, reproducing the SCOP and CATH classifications with a sensitivity of 65% at a specificity of 90%. We applied the new approach to enhance our comprehensive structural classification of ?-helical membrane proteins (CAMPS), which is primarily based on sequence and topology similarity, in order to find protein clusters that describe the same fold in the absence of sequence similarity. The total of 151 helix architectures were delineated for proteins with more than four transmembrane segments. Interestingly, we observed that proteins with 8 and more transmembrane helices correspond to fewer different architectures than proteins with up to 7 helices, suggesting that in large membrane proteins the evolutionary tendency to re-use already available folds is more pronounced.

| S-EPMC3808409 | biostudies-literature

Coiled coils 9-to-5: rational <i>de novo</i> design of α-helical barrels with tunable oligomeric states.

Project description:The rational design of linear peptides that assemble controllably and predictably in water is challenging. Short sequences must encode unique target structures and avoid alternative states. However, the non-covalent forces that stabilize and discriminate between states are weak. Nonetheless, for α-helical coiled-coil assemblies considerable progress has been made in rational de novo design. In these, sequence repeats of nominally hydrophobic (h) and polar (p) residues, hpphppp, direct the assembly of amphipathic helices into dimeric to tetrameric bundles. Expanding this pattern to hpphhph can produce larger α-helical barrels. Here, we show that pentameric to nonameric barrels are accessed by varying the residue at one of the h sites. In peptides with four L/I-K-E-I-A-x-Z repeats, decreasing the size of Z from threonine to serine to alanine to glycine gives progressively larger oligomers. X-ray crystal structures of the resulting α-helical barrels rationalize this: side chains at Z point directly into the helical interfaces, and smaller residues allow closer helix contacts and larger assemblies.

| S-EPMC8503928 | biostudies-literature

Rational design of a ligand-based antagonist of jasmonate perception

Project description:The phytohormone (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a major regulator of developmental and stress responses in plants. The perception of JA-Ile involves the formation of a ternary complex with the F-box protein COI1 and a member of the JAZ family of co-repressors, which leads to JAZ degradation. Coronatine (COR) is a bacterial phytotoxin that functionally mimics JA-Ile and interacts with the co-receptor COI1-JAZ complex with higher affinity than JA-Ile. Based on the crystal structure of the co-receptor, we designed ligand derivatives that spatially impede the interaction of the co-receptor proteins and, therefore, should act as competitive antagonists of COR or JA-Ile. One derivative, Coronatine O-methyloxime (COR-MO), shows a strong activity preventing COI-JAZ interaction and the subsequent JAZ degradation. COR-MO efficiently reverts the effects of JA-Ile or COR treatments on JA-mediated responses, such as anthocyanin accumulation, root-growth inhibition and gene expression in Arabidopsis plants. Moreover, it potentiates plant resistance preventing the effect of bacterially produced COR during Pseudomonas syringae infections in different plant species. In addition to the utility of COR-MO for Plant Biology research, our results underscore its biotechnological and agronomical potential for a safer and sustainable agriculture. Two-condition experiment, Col-0 vs Col-0 plants treated 2h with Coronatine 0-methyloxime (COR-MO) and Col-0 plants treated 2h with Coronatine vs Col-0 plants treated 2h with Coronatine plus COR-MO. Biological replicates: 4 control and 4 treated replicates

2014-06-20 | E-GEOD-56027 | biostudies-arrayexpress

Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein-Protein Interactions.

Project description:Novel unprecedented helical foldamers have been effectively designed and synthesized. The homogeneous right-handed d-sulfono-γ-AApeptides represent a new generation of unnatural helical peptidomimetics, which have similar folding conformation to α-peptides, making them an ideal molecular scaffold to design α-helical mimetics. As demonstrated with p53-MDM2 PPI as a model application, the right-handed d-sulfono-γ-AApeptides reveal much-enhanced binding affinity compared to the p53 peptide. The design of d-sulfono-γ-AApeptides may provide a new and alternative strategy to modulate protein-protein interactions.

| S-EPMC8204676 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data