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Linus Pauling in 1950 published a three-dimensional model for a universal protein secondary structure motif which he initially called the alpha-spiral. Jack Dunitz, then a postdoc in Pauling's lab suggested to Pauling that the term helix is more accurate than spiral when describing the right-handed peptide and protein coiled structures. Pauling agreed, hence the rise of the alpha-helix, and, by extension, the ‘double helix’ structure of DNA. Although structural biologists and protein chemists are familiar with varying polar and apolar characters of amino acids in alpha-helices, to non-experts the three chemically distinct alpha-helix types classified here may hide in plain sight.

Flower malformation represented by phyllody is a common symptom of phytoplasma infection induced by a novel family of phytoplasma effectors called phyllogens. Despite the accumulation of functional and structural phyllogen information, the molecular mechanisms of phyllody have not yet been integrated with their evolutionary aspects due to the limited data on their homologs across diverse phytoplasma lineages. Here, we developed a novel universal PCR‐based approach to identify 25 phytoplasma phyllogens related to nine “Candidatus Phytoplasma” species, including four species whose phyllogens have not yet been identified. Phylogenetic analyses showed that the phyllogen family consists of four groups (phyl‐A, ‐B, ‐C, and ‐D) and that the evolutionary relationships of phyllogens were significantly distinct from those of phytoplasmas, suggesting that phyllogens were transferred horizontally among phytoplasma strains and species. Although phyllogens belonging to the phyl‐A, ‐C, and ‐D groups induced phyllody, the phyl‐B group lacked the ability to induce phyllody. Comparative functional analyses of phyllogens revealed that a single amino acid polymorphism in phyl‐B group phyllogens prevented interactions between phyllogens and A‐ and E‐class MADS domain transcription factors (MTFs), resulting in the inability to degrade several MTFs and induce phyllody. Our finding of natural variation in the function of phytoplasma effectors provides new insights into molecular mechanisms underlying the aetiology of phytoplasma diseases. Comparison of phyllogen, a phyllody‐inducing effector family, revealed its molecular evolution and functional variation attributed to a single amino acid polymorphism governing the phyllody symptoms of phytoplasma infection.

BAR (Bin/Amphiphysin/Rvs) domains and amphipathic α‐helices (AHs) are believed to be sensors of membrane curvature thus facilitating the assembly of protein complexes on curved membranes. Here, we used quantitative fluorescence microscopy to compare the binding of both motifs on single nanosized liposomes of different diameters and therefore membrane curvature. Characterization of members of the three BAR domain families showed surprisingly that the crescent‐shaped BAR dimer with its positively charged concave face is not able to sense membrane curvature. Mutagenesis on BAR domains showed that membrane curvature sensing critically depends on the N‐terminal AH and furthermore that BAR domains sense membrane curvature through hydrophobic insertion in lipid packing defects and not through electrostatics. Consequently, amphipathic motifs, such as AHs, that are often associated with BAR domains emerge as an important means for a protein to sense membrane curvature. Measurements on single liposomes allowed us to document heterogeneous binding behaviour within the ensemble and quantify the influence of liposome polydispersity on bulk membrane curvature sensing experiments. The latter results suggest that bulk liposome‐binding experiments should be interpreted with great caution.

α-Helical antimicrobial peptides (AMPs) generally have facially amphiphilic structures that may lead to undesired peptide interactions with blood proteins and self-aggregation due to exposed hydrophobic surfaces. Here we report the design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. The radially amphiphilic structure enables the polypeptide to bind effectively to the negatively charged bacterial surface and exhibit high antimicrobial activity against both gram-positive and gram-negative bacteria. Moreover, the shielding of the hydrophobic core by the charged exterior shell decreases nonspecific interactions with eukaryotic cells, as evidenced by low hemolytic activity, and protects the polypeptide backbone from proteolytic degradation. The radially amphiphilic polypeptides can also be used as effective adjuvants, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude. Designing AMPs bearing this unprecedented, unique radially amphiphilic structure represents an alternative direction of AMP development; radially amphiphilic polypeptides may become a general platform for developing AMPs to treat drug-resistant bacteria.

Control of plant viruses by cross‐protection is limited by the availability of effective protective strains. Incorporation of an NIa‐protease processing site in the extreme N‐terminal region of the helper component protease (HC‐Pro) of turnip mosaic virus (TuMV) resulted in a mutant virus TuHNDI that induced highly attenuated symptoms. Recombination analysis verified that two variations, F7I mutation and amino acid 7‐upstream‐deletion, in HC‐Pro co‐determined TuHNDI attenuation. TuHNDI provided complete protection to Nicotiana benthamiana and Brassica campestris subsp. chinensis plants against infection by the severe parental strain. Aphid transmission tests revealed that TuHNDI was not aphid‐transmissible. An RNA silencing suppression (RSS) assay by agroinfiltration suggested the RSS‐defective nature of the mutant HC‐Pro. In the context (amino acids 3–17) encompassing the two variations of HC‐Pro, we uncovered an FWKG−α‐helix 1 (αH1) element that influenced the functions of aphid transmission and RSS, whose motifs were located far downstream. We further demonstrated that HC‐Pro F7 was a critical residue on αH1 for HC‐Pro functions and that reinstating αH1 in the RSS‐defective HC‐Pro of TuHNDI restored the protein's RSS function. Yeast two‐hybrid and bimolecular fluorescence complementation assays indicated the FWKG−αH1 element as an integral part of the HC‐Pro self‐interaction domain. The possibility of regulation of the mechanistically independent functions of RSS and aphid transmission by the FWKG−αH1 element is discussed. Extension of TuMV HC‐Pro FWKG−αH1 variations to another potyvirus, zucchini yellow mosaic virus, also generated nonaphid‐transmissible cross‐protective mutant viruses. Hence, the modification of the FWKG−αH1 element can generate effective attenuated viruses for the control of potyviruses by cross‐protection. The HC‐Pro extreme N‐terminal region FWKG−αH1 element, an integral part of the HC‐Pro self‐interaction domain, influences multiple functions of HC‐Pro: symptom expression, RNA silencing suppression, and aphid transmission.

The specificity of the available experimentally determined structures of amyloid forms is expressed primarily by the two- and not three-dimensional forms of a single polypeptide chain. Such a flat structure is possible due to the β structure, which occurs predominantly. The stabilization of the fibril in this structure is achieved due to the presence of the numerous hydrogen bonds between the adjacent chains. Together with the different forms of twists created by the single R- or L-handed α-helices, they form the hydrogen bond network. The specificity of the arrangement of these hydrogen bonds lies in their joint orientation in a system perpendicular to the plane formed by the chain and parallel to the fibril axis. The present work proposes the possible mechanism for obtaining such a structure based on the geometric characterization of the polypeptide chain constituting the basis of our early intermediate model for protein folding introduced formerly. This model, being the conformational subspace of Ramachandran plot (the ellipse path), was developed on the basis of the backbone conformation, with the side-chain interactions excluded. Our proposal is also based on the results from molecular dynamics available in the literature leading to the unfolding of α-helical sections, resulting in the β-structural forms. Both techniques used provide a similar suggestion in a search for a mechanism of conformational changes leading to a formation of the amyloid form. The potential mechanism of amyloid transformation is presented here using the fragment of the transthyretin as well as amyloid Aβ.

Biopolymer‐driven supramolecular chirality in aqueous media has gained significant advancements in hierarchical chiral nanostructures. However, researches on the aqueous circularly polarized luminescence (CPL) induced by supramolecular self‐assembly and its mechanism have been rarely reported. Herein, we explore the hierarchical chirality transfer in self‐assembled fluorescent homopolypeptide systems showing aqueous CPL, and unveil an α‐helix‐dominated CPL regulation mechanism.  A relationship is established between molecular structure (degree of polymerization, DP), supramolecular assembly (self‐assembly temperature, TSA), and resulting CPL properties. The stabilization for the homopolypeptide α‐helix by increasing DP and decreasing TSA enables efficient chirality transfer from the polypeptide backbone to its terminal chromophore, thereby improving CPL properties. Our work elucidates the critical role of α‐helix control in aqueous CPL systems, providing insights for designing biocompatible and tunable CPL‐active nanomaterials. We explore the hierarchical chirality transfer in self‐assembled fluorescent homopolypeptide systems for achieving aqueous circularly polarized luminescence (CPL), and reveal the α‐helix‐dominated CPL regulation mechanism during the self‐assembly process .

Cyclic lipodepsipeptides (CLiPs) from Pseudomonas are membrane‐targeting specialized metabolites with diverse ecological roles and antimicrobial activities. Over the past decades, significant efforts have been made to reveal their chemical constitution and configuration, thus providing the starting point to establishing structure–function correlations, deriving molecular‐level understanding of their mode of action, and ultimately harnessing their potential in plant biocontrol and clinical applications. The sheer diversity in chemical structures, combined with a few scattered reports of 3D structures, has limited advances in these areas. The solution conformations of eight antimicrobial, non‐phytotoxic Pseudomonas CLiPs, each representing a distinct family, are presented, obtained using a consistent NMR and molecular dynamics protocol in dodecylphosphocholine micelles. All CLiP conformations share a left‐handed α‐helix forming a stapled or catch‐pole helix motif depending on the number of residues in the macrocycle. This structural dichotomy is validated through a synthetic analogue of the naturally occurring orfamide A featuring an alternative, more constricted macrocycle. The two motifs define distinct superfamilies encompassing most known Pseudomonas CLiPs, offering a new, coherent framework for their structural classification that is also reflected in the organization of their biosynthetic gene cluster. The findings support future homology modelling and molecular design efforts for these metabolites.

Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-L-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues.

Elastin is the principal protein found in the elastic fibers of vertebrate tissues, and the water within these fibers plays a crucial role in preserving the structure and function of this hydrophobic protein. Soluble elastin was successfully obtained by repeatedly treating insoluble elastin, extracted from pig aorta, with oxalic acid. Solid-state NMR analysis was performed on the soluble elastin, focusing on conformation-dependent chemical shifts of alanine residues. This analysis revealed that cross-linked alanine residues exhibited both α-helix and random coil structures in the dry state. In contrast, the hydrated state favored random coil structures, with some distorted helices possibly present, indicating that the cross-linked configuration is relatively unstable. Similar conformational changes were observed in insoluble elastin, mirroring those found in the soluble form. Additionally, when the soluble elastin was re-cross-linked using 1,12-dodecanedicarboxylic acid and 4-hydroxyphenyl dimethylsulfonium methylsulfate, it retained a mixture of α-helix and random coil structures in the dry state. Remarkably, in the hydrated state, α-helix structures were more prominently preserved alongside random coils. These structural changes corresponded with increased stiffness of molecular chains in the hydrophobic regions compared to their state prior to re-cross-linking, even under hydrated conditions.