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Due to the amphiphilic nature of phospholipids in the cell membrane, the amphipathicity of the nanomedicine plays a crucial role in the endocytosis. However, limited biological characterization methods restrict the study of the state of nanoparticles with different amphiphilicities on cell membranes. The understanding of interaction of amphiphilic particle with cell membrane is still lacking. Herein, by combining the dissipative particle dynamics (DPD) with the framework construction of mesoporous silica nanoparticles (MSNs), we demonstrate the enhanced endocytosis induced by the hydrophobicity. DPD results confirm that the presence of hydrophobic groups on the surface of nanoparticles can disturb the integrity of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane and induce activation of phospholipids to a higher energy level, thereby facilitating the wrapping of nanoparticles. To validate the simulation findings, uniform MSNs with hydrophilic pure silica framework and two types of amphiphilic MSNs with varying hydrophilic organic groups in the framework are rationally synthesized by using different silane precursors. The obtained three kinds of MSNs show similar diameter (~ 100 nm) and mesopores (~ 2 nm), but distinct hydrophobicity/hydrophilicity ratio. The phenyl-bridged MSN with a carbon content of 27.1% exhibits enhanced cellular uptake, consistent with the theoretical simulation results. This work sheds light on how the surface amphipathicity influences endocytosis through the interaction with cell membrane. [ABSTRACT FROM AUTHOR]

Antibiotic‐resistant bacterial infections are becoming a serious health issue and will cause 10 million deaths per year by 2050. As a result, the development of new antimicrobial agents is urgently needed. Antimicrobial peptides (AMPs) are found in the innate immune systems of various organisms to effectively fend off invading pathogens. In this study, we designed a series of AMPs (THL‐2‐1 to THL‐2‐9) with centrosymmetric and amphipathic properties, through substituting different amino acids on the hydrophobic side and at the centrosymmetric position to improve their antimicrobial activity. The results showed that leucine as a residue on the hydrophobic side of the peptide could enhance its antimicrobial activity and that glutamic acid as a centrosymmetric residue could increase the salt resistance of the peptide. Thus, the THL‐2‐3 peptide (KRLLRELKRLL‐NH2) showed the greatest antimicrobial activity (MIC90 of 16 μM) against Gram‐negative bacteria and had the highest salt resistance and cell selectivity among all the designed peptides. In summary, the results of this study provide useful references for the design of AMPs to enhance antimicrobial activity. [ABSTRACT FROM AUTHOR]

A novel amphiphilic silicon-polyurethane antifouling polymer was synthesized with PDMS as the main chain and hydrophilic polymer as the side chain. With N-vinylpyrrolidone and butyl acrylate as raw materials, hydrophilic side chains were synthesized by free radical copolymerization and introduced into the silicone polyurethane system as chain extenders. Due to the hydrogen bond interaction between carbamate bonds, the prepared silicone-polyurethane polymer has high mechanical properties (tensile strength > 14 MPa, elongation at break > 1 200%) and high substrate adhesion (> 1 MPa). After introducing hydrophilic side chain, the polymer still has a low surface energy (24. 1 mJ/m²), and the antibacterial adhesion rate to Pseudomonas was 98%. In addition, MS software was used to simulate the number of hydrogen bonds and free volume molecular structure, which explained that the introduction of hydrophilic side chains led to the decline of mechanical properties because the macromolecular side chains weakened the interaction between polymer segments. [ABSTRACT FROM AUTHOR]

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Peptides have been widely studied for their good biocompatibility and diverse structural characteristics. Amphiphilic peptides, which have the special structure of hydrophilic one end and hydrophobic the other and self-assembly property, have a wide range of biological functions. Thus amphiphilic peptides become the focus of this paper. Based on the literature research and our previous study on self-designed amphiphilic peptides, this paper describes the design and structure of three kinds of amphiphilic peptides, and reviews their application in antibacterial, antitumor, tissue regeneration and drug carrier from single molecules to nanoparticles. The relationship between their structures, responsiveness, self-assembly and applications have been well represented. Amphiphilic peptides show significant advantages in smart materials that present a bright development prospect in biomedicine. This review will provide a theoretical basis for the design of functional peptides.

[Display omitted] • Antimicrobial peptides (AMPs) can have antibacterial, antifungal, antiviral and anti-inflammatory activities. • Net charge, hydrophobicity, and amino acid sequence can affect AMPs function. • Modification with other functional groups can also influence the AMPs activities. Proteins and peptides, as polypeptide chains, have usually got unique conformational structures for effective biological activity. Antimicrobial peptides (AMPs) are a group of bioactive peptides, which have been increasingly studied during recent years for their promising antibacterial, antifungal, antiviral and anti-inflammatory activity, as well as, other esteemed bioactivities. Numerous AMPs have been separated from a wide range of natural resources, or produced in vitro through chemical synthesis and recombinant protein expression. Natural AMPs have had limited clinical application due to several drawbacks, such as their short half-life due to protease degradation, lack of activity at physiological salt concentrations, toxicity to mammalian cells, and the absence of suitable methods of delivery for the AMPs that are targeted and sustained. The creation of synthetic analogs of AMPs would both avoid the drawbacks of the natural analogs and maintain or even increase the antimicrobial effectiveness. The structure–activity relationship of discovered AMPs or their derivatives facilitates the development of synthetic AMPs. This review discovered that the relationship between the activity of AMPs and their positive net charge, hydrophobicity, and amino acid sequence and the relationship between AMPs' function and other features like their topology, glycosylation, and halogenation. [ABSTRACT FROM AUTHOR]

• A novel approach for the high-valued C 6+ alcohols production was provided. • An efficient strategy for modulating the amphipathicity of catalysts was demonstrated. • The NiSn@C/TiO 2 -1 displays a selectivity and yield of C 6+ alcohols of 57.5 and 40.6 %. Aqueous ethanol upgrading has attracted great attention for producing high-valued higher alcohols. Nevertheless, the chain growth for higher alcohol production involving water–oil biphase reaction, is usually limited by the traditional single-phase (hydrophilic or lipophilic) catalyst, leading to poor selectivity of C 6+ alcohols. Herein, we demonstrate that modulating the surface amphipathicity of the active Ni-Sn composite nanoparticles by using hybrid carbon shell and TiO 2 support significantly boosted its catalytic performance. A high ethanol conversion of 70.6 % and excellent C 6+ alcohols selectivity of 57.5 % was achieved. Deep studies show that the enhanced catalytic performance was mainly originated from the facilitated emulsion catalysis by the amphiphilic NiSn@C-TiO 2 catalyst, by which the reaction process from aqueous ethanol self-coupling to intermolecular cross-coupling at the oil/water interface was dramatically accelerate. This work developed a novel emulsion catalyst for water/oil biphase interface catalysis, approaching highly efficient production of high-valued higher alcohols from direct upgrading of aqueous ethanol. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are potential therapeutic agents against bacteria. We recently showed that a rationally designed AMP, termed Stripe, with an amphipathic distribution of native cationic and hydrophobic amino acids on its helical structure exhibited potent antimicrobial activity against Gram‐positive and Gram‐negative bacteria with negligible hemolytic activity and cytotoxicity. In this study, the structure–activity relationship of Stripe was elucidated by designing a series of antimicrobial peptides whereby amino acid residues of Stripe were exchanged with helix‐destabilizing sarcosine residues. Stripe 1–5 peptides with hydrophobic amino acids substituted with sarcosine were predominantly unstructured and showed no antimicrobial activity, except against Escherichia coli (E. coli) (DH5α) cells. The activity against E. coli (DH5α) cells and the helicity of Stripe 1–5 peptides decreased concomitantly as the number of sarcosine residue substitutions increased. Stripe 1–5 peptides showed no hemolytic activity or cytotoxicity. The results indicate that sarcosine substitutions provide an approach to study the structure–activity relationship of helical AMPs, and the helicity of Stripe is an important feature defining its activity. [ABSTRACT FROM AUTHOR]

Amphiphilic carbon nitride (g-C 3 N 4) was decorated onto reduced graphene oxide (rGO) to obtain rGO-g-C 3 N 4 composites as excellent adsorbents for the removal of aromatic organic compounds from industrial wastewater. The as obtained rGO-g-C 3 N 4 composites are effective adsorbents for organic compounds due to the amphiphilic g-C 3 N 4. We propose a new adsorption model using an amphiphilic additive which can enhance the water accessibility and hydrophobic interactions between rGO with organic compounds in aqueous media. Where, even water-soluble organic molecules like rhodamine B (RhB) have a high adsorption capability for the rGO-g-C 3 N 4 (520 mg g−1). Molecular dynamics simulations were used to investigate the interactions between RhB and rGO-g-C 3 N 4 and indicated that amphiphilic g-C 3 N 4 accelerates the adsorption process. In addition, the amphipathic adsorption approach is enhanced as the salinity of water increases, which can offer great operational flexibility and versatility. This research demonstrates that the highly efficient interactions between aromatic organic molecules and amphiphilic carbon-based nanomaterials can be used for practical applications. [Display omitted] • An amphipathic strategy was developed for organic pollutants removal. • rGO-g-C 3 N 4 exhibited excellent adsorption performance for aromatic organic pollutants. • Molecular dynamics simulation verified amphipathicity enhanced adsorption mechanism. • Investigation of the rGO-g-C 3 N 4 absorption behavior of GO-g-C 3 N 4 under complex conditions. • A rGO-g-C 3 N 4 membrane was fabricated and tested using lab-scale cross flow experiments. [ABSTRACT FROM AUTHOR]

Amphipathicity is a critical characteristic of helical antimicrobial peptides (AMPs). The hydrophilic region, primarily composed of cationic residues, plays a pivotal role in the initial binding to negatively charged components on bacterial membranes through electrostatic interactions. Subsequently, the hydrophobic region interacts with hydrophobic components, inducing membrane perturbation, ultimately leading to cell death, or inhibiting intracellular function. Due to the extensive diversity of natural and synthetic AMPs with regard to the design of amphipathicity, it is complicated to study the structure-activity relationships. Therefore, this work aims to categorize the common amphipathic design and investigate their impact on the biological properties of AMPs. Besides, the connection between current structural modification approaches and amphipathic styles was also discussed., (© 2024 Wiley‐VCH GmbH.)

Amphipathicity has traditionally been considered to be essential for the de novo design or systematic optimization of antimicrobial peptides (AMPs). However, the current research methods to study the relationship between amphiphilicity and antimicrobial activity are inappropriate, because the key parameters (hydrophobicity, positive charge, etc.) and secondary structure of AMPs are changed. To systematically and accurately study the effects of amphiphilicity on antimicrobial properties of AMPs, we designed parallel series of AMPs with a different order of amino acids in a sequence composed only of Arg and either Trp (WR series) or Leu (LR series), under conditions in which other vital parameters were fixed. Furthermore, based on the WR and LR peptides that can form stable amphiphilic β-sheet structures in the anionic membrane-mimetic environment, we found that high β-sheet amphipathic was accompanied by strong antimicrobial activity. Of such peptides, W5 ([RW]4W) and L5 ([RL]4L) with a nicely amphipathic β-sheet structure possessed the optimal therapeutic index. W5 and L5 also exhibited high stability in vitro and a potent membrane-disruptive mechanism. These results suggest that the alternate arrangement of hydrophobic and hydrophilic residues to form a stable amphipathic β-sheet structure is an essential factor that significantly affects the antimicrobial properties.

Amphipathicity has traditionally been considered to be essential for the de novo design or systematic optimization of antimicrobial peptides (AMPs). However, the current research methods to study the relationship between amphiphilicity and antimicrobial activity are inappropriate, because the key parameters (hydrophobicity, positive charge, etc.) and secondary structure of AMPs are changed. To systematically and accurately study the effects of amphiphilicity on antimicrobial properties of AMPs, we designed parallel series of AMPs with a different order of amino acids in a sequence composed only of Arg and either Trp (WR series) or Leu (LR series), under conditions in which other vital parameters were fixed. Furthermore, based on the WR and LR peptides that can form stable amphiphilic β-sheet structures in the anionic membrane-mimetic environment, we found that high β-sheet amphipathic was accompanied by strong antimicrobial activity. Of such peptides, W5 ([RW]4W) and L5 ([RL]4L) with a nicely amphipathic β-sheet structure possessed the optimal therapeutic index. W5 and L5 also exhibited high stability in vitro and a potent membrane-disruptive mechanism. These results suggest that the alternate arrangement of hydrophobic and hydrophilic residues to form a stable amphipathic β-sheet structure is an essential factor that significantly affects the antimicrobial properties. [ABSTRACT FROM AUTHOR]

α‐Helical membrane‐active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel‐stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water–membrane interface, a highly amphipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α‐helical membrane‐active AMPs at the water–membrane interface by optimising amphipathicity. This amphipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane‐active AMPs to be predicted. The ASP algorithm is accessible via a web interface at http://atb.uq.edu.au/asp/. [ABSTRACT FROM AUTHOR]

• PAL-Cl was prepared by a simple three-step reaction. • PAL-Cl has high demulsification efficiency at low temperatures. • PAL-Cl has outstanding acid, alkali and salt resistance. • PAL-Cl is no-toxic and environmentally friendly. The treatment of water-in-oil (W/O) emulsions has always been a challenge in the petroleum industry. In this article, a tetra-branched bicationic liquid demulsifier (PAL-Cl) was prepared. The structure of PAL-Cl was confirmed by Fourier-transform infrared spectrum (FT-IR), Nuclear magnetic resonance spectrum (NMR) and Gel permeation chromatography (GPC). Some factors affecting demulsification efficiency (DE) such as dosage, salinity, pH, temperature, etc. were explored in detail. The DE reached 96.5 % after demulsifying with 50 mg/L of PAL-Cl at 70 °C for 240 min. Especially, a relatively lower temperature of 40 °C could obtain the DE of 94.1 % with 250 mg/L of PAL-Cl for 360 min. Moreover, PAL-Cl has outstanding acid, alkali and salt resistance. In addition, the demulsification mechanism was in detail investigated by surface tension (SFT), interfacial tension (IFT), competitive adsorption experiments, coalescence time of droplets (CT), three-phase contact angle (CA), zeta potential and micrographs. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are promising therapeutic agents against bacteria. We have previously reported an amphipathic AMP Stripe composed of cationic L-Lys and hydrophobic L-Leu/L-Ala residues, and Stripe exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria. Gramicidin A (GA), composed of repeating sequences of L- and D-amino acids, has a unique β 6.3 -helix structure and exhibits broad antimicrobial activity. Inspired by the structural properties and antimicrobial activities of LD-alternating peptides such as GA, in this study, we designed Stripe derivatives with LD-alternating sequences. We found that simply alternating L- and D-amino acids in the Stripe sequence to give StripeLD caused a reduction in antimicrobial activity. In contrast, AltStripeLD, with cationic and hydrophobic amino acids rearranged to yield an amphipathic distribution when the peptide adopts a β 6.3 -helix, displayed higher antimicrobial activity than AltStripe. These results suggest that alternating L-/D-cationic and L-/D-hydrophobic amino acids in accordance with the helical structure of an AMP may be a useful way to improve antimicrobial activity and develop new AMP drugs.

The antimicrobial and hemolytic activities of R9F2С2 (P1ss), (KFF)3KС2 (P2ss), and (RAhaR)4AhaβAС2 (P3ss) (where Aha is 6-aminohexanoic acid and βA is beta-alanine) synthetic antimicrobial peptides (SAMP) with different amphipathic properties and containing the cysteine residues with free sulfhydryl groups were studied. The introduction of cysteine residues into the composition of SAMP was shown to increase their antimicrobial activity 3–7 times, while their hemolytic activity increased 2–12 times in relation to human erythrocytes for different peptides in different ways, which determined their different selectivity. The P1ss peptide with a linear type of amphipathicity showed the highest antimicrobial activity and high selectivity against the fungus Candida albicans and bacterium Staphylococcus aureus (MIC 0.5 μM; TI 52 μM). The P1ss peptide possessed not only greater antimicrobial activity against pathogenic fungus C. albicans in comparison to the P2ss peptide (MIC 3.9 μM) with the classical helical amphipathicity, but also more than three times lower hemolytic activity (MHC 26 and 8 μM, respectively). Therefore, TI for the P2ss peptide (TI 2.1) turned out to be more than 20 times lower than that for the P1ss peptide. Thus, the P1ss peptide is the most promising antimicrobial preparation among the studied SAMP. [ABSTRACT FROM AUTHOR]

• The conformational property of Bac2A peptide and its stapled counterparts are investigated systematically. • The helical wheel of Bac2A peptide is designed to enhance its hydrophobicity and hydrophobic moment. • Stapling can effectively improve the helicity, amphipathicity and activity of Bac2A peptide. • The membrane–peptide interaction dynamics can be divided into four distinct phases. The Bac2A (RLARIVVIRVAR−NH2) is a linearized counterpart of cationic cyclic peptide Bactenecin—one of the smallest naturally occurring antimicrobial peptides (AMPs), which, however, generally exhibits a low or moderate antibacterial potency against gram-positive bacteria. Here, it is found that the Bac2A and its linear derivates cannot spontaneously fold into a well-defined helical conformation in solution, thus impairing the peptide amphipathicity and antibacterial activity. Hydrocarbon stapling is rationally designed to constrain the helical conformation of these linear peptides. Atomistic dynamics simulations reveal that the membrane-penetrating course of linear and stapled peptides include four distinct phases, during which the stapled peptides can maintain in an ordered helical conformation, while linear peptides are structured from intrinsic disorder in water solution to partially helical state in membrane interior, indicating that lipid environment can help the linear peptide refolding into amphipathic helix, although the refolding process would incur a large configurational entropy penalty. The antibacterial activities of the most potent stapled peptide are determined as MIC = 7.6 and 16 µg/ml against two gram-positive Staphylococcus aureus clinical strains isolated from pyemia. The activity values are improved by 7.1-fold and 5-fold as compared to that of native Bac2A peptide with MIC = 54 and 80 µg/ml, respectively. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The properties of conventional surfactants (c-surfactants) are generally accepted to be amphipathicity-dominated, but extended surfactants (e-surfactants) are additionally polypropylene oxide (PPO)-dependent; this additional property makes us wonder how an intramolecular PPO spacer would be "extended" at various interfaces and what is responsible for the excellent all-round properties of e-surfactants. A series of novel sodium medium alkyl chain PPO- b -PEO sulfates (2-ethylhexyl polypropylene oxide- block -polyethylene oxide sulfates, C 8 P p E e S) were designed, synthesized and structurally identified. Tensiometry was applied to estimate the surfactant shape at the air/water surface. Surface tension, interfacial tension, emulsifying power, electrolyte tolerance, adsorption onto oil sands and thermal hydrolysis stability were measured to evaluate the effect of the PPO coil on the interfacial and micellar properties of the e-surfactants. On the basis of obtaining greater values for e-surfactants than c-surfactants for both surface area (a m) per surfactant molecule and the corresponding shape factor (S), we were surprised to find that e-surfactants form a rugby ball shape not only at the air/water surface but also at the oil/water interface; this result is potentially explained by the PPO spacer coiling and collapsing to produce dense packing at the monolayer adsorption, which is rationally borrowed by other interfaces. Many positive or negative correlations were observed between the interfacial/micellar properties of C 8 P p E e S and a m values, which seems that the surfactant shape dominants the properties of the e-surfactants. In fact, the properties of C 8 P p E e S are dominated by the dynamic amphipathicity and assisted by the rugby ball shape of the molecules because of both being driven by the dynamic biphasic affinity of the PPO coil in response to the external environment; these findings provide soft interfacial materials specially adapted for surfactant flooding. [ABSTRACT FROM AUTHOR]

Abstract In the direct cell membrane penetration, arginine-rich cell-penetrating peptides are thought to penetrate into cells across the hydrophobic lipid membranes. To investigate the effect of the amphipathic property of arginine-rich peptide on the cell-penetrating ability, we designed a novel amphipathic cell-penetrating peptide, A2-17, and its derivative, A2-17KR, in which all lysine residues are substituted with arginine residues, based on the glycosaminoglycan binding region in the N-terminal α-helix bundle of human apolipoprotein E. Isothermal titration calorimetry showed that A2-17 variants have a strong ability to bind to heparin with high affinity. Circular dichroism and tryptophan fluorescence measurements demonstrated that A2-17 variants bind to lipid vesicles with a structural change from random coil to amphipathic α-helix, being inserted into the hydrophobic membrane interiors. Flow cytometric analysis and confocal laser scanning microscopy demonstrated the great cell penetration efficiency of A2-17 variants into CHO-K1 cells when incubated at low peptide concentrations (2 μM or less), suggesting that the increased amphipathicity with α-helix formation enhances the cell membrane penetration ability of arginine-rich peptides. Interestingly, A2-17KR exhibited lower efficiency of cell membrane penetration compared to A2-17 despite of their similar binding affinity to lipid membranes. Since high peptide concentrations (typically >10 μM) are usually prerequisite for efficient cell penetration of arginine-rich peptides, A2-17 is a unique amphipathic cell-penetrating peptide that exhibits an efficient cell penetration ability even at low peptide concentrations. Graphical abstract Unlabelled Image Highlights • An amphipathic cell-penetrating peptide, A2-17, is newly designed. • A2-17 binds to both heparin and lipid membranes with high affinity. • A2-17 forms amphipathic α-helix upon binding to heparin and lipid membranes. • A2-17 efficiently penetrates cell membranes even at low peptide concentrations. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Structural characterization of BMAP-28(1–18), a potent bovine myeloid antimicrobial peptide can aid in understanding its mechanism of action at molecular level. We report NMR structure of the BMAP-28(1–18) and its mutated analogue mut BMAP18 in SDS micelles. Structural comparison of the peptides bound to SDS micelles and POPE-POPG vesicles using circular dichroism, suggest that structures in the two lipid preparations are similar. Antimicrobial assays show that even though both these peptides adopt helical conformation, BMAP-28(1–18) is more potent than mut BMAP18 in killing bacterial cells. Our EM images clearly indicate that the peptides target the bacterial cell membrane resulting in leakage of its contents. The structural basis for difference in activity between these peptides was investigated by molecular dynamics simulations. Inability of the mut BMAP18 to retain its helical structure in presence of POPE:POPG membrane as opposed to the BMAP-28(1–18) at identical peptide/lipid ratios could be responsible for its decreased activity. Residues Ser5, Arg8 and Arg12 of the BMAP-28(1–18) are crucial for its initial anchoring to the bilayer. We conclude that along with amphipathicity, a stable secondary structure that can promote/initiate membrane anchoring is key in determining membrane destabilization potential of these AMPs. Our findings are a step towards understanding the role of specific residues in antimicrobial activity of BMAP-28(1–18), which will facilitate design of smaller, cost-effective therapeutics and would also help prediction algorithms to expedite screening out variants of the parent peptide with greater accuracy. [ABSTRACT FROM AUTHOR]

Magainin 2 (Mag2), which was isolated from the skin of the African clawed frog, is a representative antimicrobial peptide (AMP) that exerts antimicrobial activity via microbial membrane disruption. It has been reported that the helicity and amphipathicity of Mag2 play important roles in its antimicrobial activity. We investigated and recently reported that 17 amino acid residues of Mag2 are required for its antimicrobial activity, and accordingly developed antimicrobial foldamers containing α,α-disubstituted amino acid residues. In this study, we further designed and synthesized a set of Mag2 derivatives bearing the hydrocarbon stapling side chain for helix stabilization. The preferred secondary structures, antimicrobial activities, and cell-membrane disruption activities of the synthesized peptides were evaluated. Our analyses revealed that hydrocarbon stapling strongly stabilized the helical structure of the peptides and enhanced their antimicrobial activity. Moreover, peptide 2 stapling between the first and fifth position from the N-terminus showed higher antimicrobial activity than that of Mag2 against both gram-positive and gram-negative bacteria without exerting significant hemolytic activity. To investigate the modes of action of tested peptides 2 and 8 in antimicrobial and hemolytic activity, electrophysiological measurements were performed.

Defense peptides are small amphipathic molecules that exhibit antimicrobial, antitumor, antiviral, and immunomodulatory properties. This review summarizes current knowledge on the mechanisms of antimicrobial activity of cationic and anionic defense peptides, indicating peptide-based as well as microbial cell-based factors affecting this activity. The peptide-based factors include charge, hydrophibicity, and amphipathicity, whereas the pathogen-based factors are membrane lipid composition, presence of sterols, membrane fluidity, cell wall components, and secreted factors such as extracellular proteinases. Since defense peptides have been considered very promising molecules that could replace conventional antibiotics in the era of drug-resistant pathogens, the issue of microbial resistance to antimicrobial peptides (AMPs) is addressed. Furthermore, selected approaches employed for optimization and de novo design of effective AMPs based on the properties recognized as important for the function of natural defense peptides are presented.

Membrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with identical pharmacophores but different side chains; five of them were found inactive. To address the possibility that their activity is limited by the permeation step, we calculated polarity, measured surface activity and the ability to insert into the phospholipid monolayers. The partitioning of PL and the analogs into the cytoplasmic membrane of E. coli was assessed by activation curve shifts of a re-engineered mechanosensitive channel, MscS, in patch-clamp experiments. Despite predicted differences in polarity, the affinities to lipid monolayers and native membranes were comparable for most of the analogs. For PL and the di-myrtenyl analog QD-11, both carrying bulky sidechains, the affinity for the native membrane was lower than for monolayers (half-membranes), signifying that intercalation must overcome the lateral pressure of the bilayer. We conclude that the biological activity among the studied PL analogs is unlikely to be limited by their membrane permeability. We also discuss the capacity of endogenous tension-activated channels to detect asymmetric partitioning of exogenous substances into the native bacterial membrane and the different contributions to the thermodynamic force which drives permeation.

Although membrane lytic antimicrobial peptides (AMPs) show enormous potential for addressing mounting global antibiotic resistance, therapeutic applications are hindered by their weak antimicrobial activity, high toxicity, salt sensitivity and poor understanding of structure-activity relationships. To investigate the effects of different parameters on the biological activities of AMPs, a rational approach was adopted to design a series of short cationic α-helical peptides comprising the Ac-WxKyWxzzyKxWyK-NH 2 sequence, where x: cationic residues (Arg or Lys), y: hydrophobic residues (Ala, Val, Ile or Leu), and zz: β-turn (rigid D-Pro-Gly turn or flexible Gly-Gly turn). The peptides showed a more helical structure as the concentration of membrane-mimetic solution increased. The peptide RL with a central D-Pro-Gly turn (x: Arg, y: Lys, zz = D-Pro-Gly) exhibited broad-spectrum antimicrobial activities (2–8 μM) against ten types of clinically relevant microorganisms and even maintained its activity in the presence of physiological salts and showed excellent selectivity toward bacterial cells over human red blood cells and mammalian cells. However, the toxicity was increased after the removal of D-Pro-Gly turn. Additionally, the bactericidal activity was reduced when the D-Pro-Gly turn was replaced by a Gly-Gly turn. Fluorescence spectroscopy and electron microscopy analyses indicated that RL and its derivatives killed microbial cells by permeabilizing the cell membrane and damaging membrane integrity. In conclusion, these findings clearly generalized a potential method for designing or optimizing AMPs, and the peptide RL is a promising therapeutic candidate to combat antibiotic resistance. Statement of Significance We proposed a rational approach to design imperfectly amphiphilic peptides and identified RL (Ac-WRKLWRpGLKRWLK-NH 2 ) in particular that shows strong antibacterial properties, low toxicity and high salt resistance. The β-turn unit inserted into the central position of cationic α-helical peptides, especially the D-Pro-Gly turn, significantly increase the cell selectivity of the synthetic amphiphiles. The findings demonstrate a potential method for designing and/or optimizing AMPs, which would facilitate the development of strategies to design peptide-based antimicrobial biomaterials in a variety of biotechnological and clinical applications. [ABSTRACT FROM AUTHOR]

Chiral, ionic C 2 -symmetric binaphthyl fluorophores with amphipathic property can emit circularly polarized luminescence (CPL) in the near-UV region when dissolved in either water or methanol. Despite the same axial chirality ( R or S ) of the binaphthyl units, the open- and closed-style fluorophores induced sign inversion of CPL and circular dichroism (CD) signals in water. The dihedral angle of the binaphthyl C 2 -axis appears to determine the signs of CPL and CD signals even in water. [ABSTRACT FROM AUTHOR]

It has been unclear to which antimicrobial activities (e.g., anti-gram-positive bacterial, anti-gram-negative bacterial, antifungal, antiparasitic, and antiviral activities) of antimicrobial peptides (AMPs) a given physiochemical property matters most. This is the first computational study using large-scale AMPs to examine the relationships between antimicrobial activities and two major physiochemical properties of AMPs--amphipathicity and net charge. The results showed that among all kinds of antimicrobial activities, amphipathicity and net charge best differentiated between AMPs with and without anti-gram-negative bacterial activities. In terms of amphipathicity and charge, all the AMPs whose activities were significantly associated with amphipathicity and net charge were alike except those with anti-gram-positive bacterial activities. Furthermore, the higher the amphipathic value, the greater the proportion of AMPs possessing both antibacterial and antifungal activities. This dose-response-like pattern suggests a possible causal relationship--dual antibacterial and antifungal activities of AMPs may be attributable to amphipathicity. These novel findings could be useful for identifying potent AMPs computationally. [ABSTRACT FROM AUTHOR]

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy. [ABSTRACT FROM AUTHOR]

The mutant huntingtin protein (mHtt) fragments with expanded polyglutamine sequence forms microscopically visible aggregates in neurons, a hallmark of Huntington's disease (HD). The aggregation process and aggregates are possible targets of therapeutic intervention in HD. Owing to the lack of treatment and cure, the patients die within 15-20 years after the disease onset. Therefore, discovering therapeutic molecules that may either inhibit the aggregation mechanism or downregulate the toxic effects of mHtt are highly needed. This study demonstrates the design and use of peptide inhibitors based on the role played by the N-terminal seventeen amino acid sequence (NT17) of huntingtin fragment in its aggregation. Fug-NT17 (Fugu), Xen-NT17 (Xenopus), Dro-NT17 (Drosophila), Aib-NT17, and Pro-NT17 sequences were tested for their ability to inhibit aggregation. Among them, the first three are the sequence variants of human NT17 from evolutionarily distant organisms and the latter two are the analogs of human NT17-containing aminoisobutyric acid (Aib) and proline (Pro). Four out of five inhibited the aggregation of huntingtin fragment, NT17Q35P10K2 polypeptide. Data indicate that the physicochemical properties of the inhibitors play a crucial role in exhibiting the inhibitory effect. These inhibitors can be tested in cell and animal models for the preclinical evaluation in the treating of HD. [ABSTRACT FROM AUTHOR]

All eukaryotic organisms, single-celled or multi-cellular, produce a diverse array of natural anti-infective agents that, in addition to conventional antimicrobial peptides, also include proteins and other molecules often not regarded as part of the innate defences. Examples range from histones, fatty acids, and other structural components of cells to pigments and regulatory proteins. These probably represent very ancient defence factors that have been re-used in new ways during evolution. This review discusses the nature, biological role in host protection and potential biotechnological uses of some of these compounds, focusing on those from fish, marine invertebrates and marine micro-algae.

Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure–activity relationships study on Dyn A identified lead ligands 1 and 4 , along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma ( t 1/2 <1 h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand 4 afforded a cyclic Dyn A analogue 5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability ( t 1/2 >5 h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development. [ABSTRACT FROM AUTHOR]

As a unique endogenous opioid ligand, dynorphin A shows paradoxical neuroexcitatory effects at bradykinin receptors, and the effects are known to be amplified by the upregulation of dynorphin A under chronic pain and inflammatory conditions. In our earlier structure-activity relationship studies, the amphipathic dynorphin A fragment, [ Des- Arg7]- Dyn A-(4-11), was identified as a pharmacophore for the bradykinin receptors along with key structural features. Here, further modifications of the pharmacophore showed that the position of a Pro residue is also an important feature because of its role in making (or disrupting) a β-turn or 310 helix structure which is crucial for receptor recognition. [ABSTRACT FROM AUTHOR]

Membrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with identical pharmacophores but different side chains; five of them were found inactive. To address the possibility that their activity is limited by the permeation step, we calculated polarity, measured surface activity and the ability to insert into the phospholipid monolayers. The partitioning of PL and the analogs into the cytoplasmic membrane of E. coli was assessed by activation curve shifts of a re-engineered mechanosensitive channel, MscS, in patch-clamp experiments. Despite predicted differences in polarity, the affinities to lipid monolayers and native membranes were comparable for most of the analogs. For PL and the di-myrtenyl analog QD-11, both carrying bulky sidechains, the affinity for the native membrane was lower than for monolayers (half-membranes), signifying that intercalation must overcome the lateral pressure of the bilayer. We conclude that the biological activity among the studied PL analogs is unlikely to be limited by their membrane permeability. We also discuss the capacity of endogenous tension-activated channels to detect asymmetric partitioning of exogenous substances into the native bacterial membrane and the different contributions to the thermodynamic force which drives permeation. [ABSTRACT FROM AUTHOR]

Photofrin ® is a clinically useful photosensitizer of photodynamic therapy (PDT) used for cancer treatment, but has some disadvantages, including its weak absorbance when excited at 630 nm. Hence, the development of novel photosensitizers with greater than 630 nm absorbance is required. In addition, photosensitizers must have suitable balance between lipophilicity and hydrophilicity to allow for selective accumulation in tumor cells. Herein, we describe the design and synthesis of a novel perfluorinated phthalocyanine/galactose conjugate 1a suitable for use as a PDT agent. Our novel phthalocyanine/galactose conjugate 1a displays absorption at 600–750 nm. Four of its peripheral galactopyranosyl moieties resulted in improved water solubility confirmed by a 1-octanol/water partition coefficient log P value. Moreover, 12 fluorine atoms at the peripheral position of 1a simultaneously endowed the macrocycle with suitable hydrophobicity. In vitro biological activity of our perfluorinated phthalocyanine/galactose conjugate 1a showed a much more efficient photo-dynamic effect than the non-fluorinated phthalocyanine/galactose counterpart 1b . This is one of the clear examples of fluorine effect on biological activity. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) serve as a defense mechanism within multicellular organisms and are attracting increasing attention because of their potential application in the treatment of multidrug-resistant infections. Amphipathicity has long been believed to be the most important consideration for the structural modification and design of both naturally occurring and synthetic AMPs. Previous studies indicated that disruptive amphipathicity formed by replacing the paired charged amino acid residues on the polar face of an amphipathic helix with tryptophan residues linked with hydrogen bonds on the basis of α-helical protein folding principles endowed the AMPs with increased cell selectivity. In an attempt to augment and hone this strategy further, we designed a series of imperfect amphipathic peptides by placing different types of amino acid residues at the hydrogen bond linked positions of α-helix structures to characterize their antimicrobial properties and mechanism of action. The d -Trp-substituted sequence (PRW4-d) showed greater antimicrobial potency than Cys-(C4), Asp-(D4), Ile-(I4), and Pro-(P4) substituted sequences, comparable to the l -Trp-substituted parent sequence (PRW4). Furthermore, the total replacement of Lys residues with Arg residues along the peptide sequence (PRW4-R) exhibited enhanced antimicrobial activity and cell selectivity. In addition, no cytotoxicity was observed among these synthetic peptides. PRW4-d and PRW4-R maintained their activities in the presence of physiological salts and human serum. The fluorescence spectroscopy, flow cytometry, and electron microscopy observations indicated that the optimized sequences exhibited excellent antimicrobial potency by inducing cytoplasmic membrane potential loss, membrane permeabilization and disruption. Collectively, the results could be useful for designing short AMPs with great antimicrobial activity and cell selectivity. [ABSTRACT FROM AUTHOR]

It has been shown that under chronic pain or nerve injury conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) to cause hyperalgesia in the spinal cord. Thus BRs antagonist can modulate hyperalgesia by blocking Dyn A’s interaction with the BRs in the central nervous system. In our earlier structure–activity relationship (SAR) study, [des-Arg 7 ]-Dyn A-(4–11) 13 was discovered as a minimum pharmacophore for rat brain BRs with its antagonist activity (anti-hyperalgesic effect) in in vivo tests using naïve or injured animals. We have pursued further modification on the [des-Arg 7 ]-Dyn A analogues and identified a key insight into the pharmacophore of the rat brain BRs: amphipathicity. [ABSTRACT FROM AUTHOR]

Due to increasing resistance of bacteria to traditional antibiotics, antimicrobial peptides are being investigated as a promising alternative. Tachyplesin, an antimicrobial peptide isolated from horseshoe crab, inhibits the growth of many different types of bacteria with its ability to permeabilize the cell membrane. Starting with a previously reported linear tachyplesin analog lacking cysteine (cysteine-deleted tachyplesin, CDT, KWFRVYRGIYRRR-CONH), this study examines the systematic deletion of the C-terminal arginines and the N-terminal lysine, addition of positively charged N-and C-terminal residues, replacement of arginine with similarly-charged lysine, and replacement of hydrophobic residues with aliphatic, aromatic, fluoro-substituted aromatic, and bicyclic amino acids to examine effects on activity. The 16 modified CDT analogs were tested for their ability to disrupt model liposomes, and minimum inhibitory concentrations were determined for gram-positive and gram-negative bacterial strains. Hemolytic activity also was assessed. Overall, results indicate that elimination of two C-terminal arginine residues results in a peptide ([des-Arg]CDT) with preserved antimicrobial activity but a reduction in hemolysis, a selectivity desirable for a therapeutic agent. Additional deletion was not tolerated, nor was addition of residues at the termini. Analysis of the 16 analogs also reveals the importance of hydrophobicity, not necessarily aromaticity, as an analog with hydrophobic isoleucine residues placed throughout the sequence ([Ile]CDT) displayed comparable antimicrobial activity to CDT with lower hemolysis, representing a promising antimicrobial peptide with lowered toxicity. [ABSTRACT FROM AUTHOR]

Developing an emulsion separation material with one-step in-situ purifying capability and improved security in applications, especially for subsequent scale-up, is valuable but remains a challenge. Herein, the amphiphilic sponge (PA@RGO@MS) was prepared via impregnation and in-situ growth of the negatively charged hydrophilic phytic acid (PA) and the hydrophobic reduced graphene oxide (RGO) on the surface of the melamine sponge (MS) and applied in emulsion purification. The mechanics, wettability, absorption performance of the PA@RGO@MS were analyzed to identify its potential for stable demulsification. Results show that the PA@RGO@MS could purify emulsions (turbidity removal rate = 99.7%; TOC removal rate = 94.14%) in-situ in one step by simple shock absorption, profited from the hydrophilic and demulsification capability of PA, oil absorption of RGO, and wide reaction and storage space of MS. Targeting the emulsion with distinct properties (density, viscosity, and concentration) of the oil phase, the PA@RGO@MS could efficiently enable the purification. Meanwhile, the powerful flame-retardant granted from PA ensures the safe shipment and storage of sponges. The favorable cyclability (turbidity removal rate > 98.5% and TOC removal rate > 89.5% after 10 cycles) and diversified operating modes enhance the practical value of the PA@RGO@MS. [Display omitted] • The PA@RGO@MS was successfully fabricated by impregnation and in-situ growth. • The PA and RGO@MS undertake the task of demulsification and oil absorption, respectively. • The PA@RGO@MS could efficiently realize one-step in-situ emulsion purification. • The PA@RGO@MS could achieve emulsion separation in multiple ways. • The PA@RGO@MS owns enhanced security during storage or transportation. [ABSTRACT FROM AUTHOR]

Abstract: Delivery of DNA to cells remains a key challenge towards development of gene therapy. A better understanding of the properties involved in stability and transfection efficiency of the vector could critically contribute to the improvement of delivery vehicles. In the present work we have chosen two peptides differing only in amphipathicity and explored how presence of cysteine affects DNA uptake and transfection efficiency. We report an unusual observation that addition of cysteine selectively increases transfection efficiency of secondary amphipathic peptide (Mgpe-9) and causes a drop in the primary amphipathic peptide (Mgpe-10). Our results point the effect of cysteine is dictated by the importance of physicochemical properties of the carrier peptide. We also report a DNA delivery agent Mgpe-9 exhibiting high transfection efficiency in multiple cell lines (including hard-to-transfect cell lines) with minimal cytotoxicity which can be further explored for in vivo applications. [Copyright &y& Elsevier]

Abstract: Antimicrobial peptides (AMPs), which are produced by multicellular organisms as a defense mechanism against competing pathogenic microbes, appear to be excellent candidates for the development of novel antimicrobial agents. Amphipathicity is traditionally believed to be crucial to the de novo design or systematic optimization of AMPs. In this study, we designed a series of short α-helical AMPs with imperfect amphipathicity to augment the arsenal of strategies and to gain further insights into their antimicrobial and hemolytic activity. These imperfectly amphipathic α-helical AMPs were designed by replacing the paired charged amino acid residues on the polar face of an amphipathic peptide with tryptophan residues on the basis of α-helical protein folding principles. PRW4, an imperfectly amphipathic α-helical AMP with hydrogen bonds formed by paired tryptophan residues, was observed to be more selective towards bacterial cells than toward human red blood cells. PRW4 was also effective against Gram-negative and Gram-positive bacteria, and fluorescence spectroscopy, flow cytometry, scanning electron microscopy and transmission electron microscopy indicated that PRW4 killed microbial cells by permeabilizing the cell membrane and damaging their membrane integrity. Therefore, disruptive amphipathicity has excellent potential for the rational design and optimization of AMPs with promising antimicrobial activities. [Copyright &y& Elsevier]

Abstract: Amphiphilic alginate esters (Alg-C n ) with different degree of substitution (DS) and hydrophobic alkyl length were synthesized by the reaction between partially protonated sodium alginate and aliphatic alcohols (octanol, dodecanol or hexadecanol) and characterized by conventional methods. The critical micelles concentration (CMC) of Alg-C n was determined by measuring the fluorescence intensity of pyrene as a fluorescent probe, conductance and surface tension (SFT). Formation and characteristics of the self-assembly micelles of Alg-C n were studied by transmission electron microscopy (TEM) and Zetasizer Nano Series method. The results indicate that CMC value and the self-assembled micelle size decreased with the increasing of the hydrophobic alkyl chain length, as the DS of Alg-C n is similar. [Copyright &y& Elsevier]

Aims To understand the structure-activity relationship of chensinin-1, a anti-microbial peptide ( AMP) with an unusual structure, and to develop novel AMPs as therapeutic agents. Methods and Results A series of chensinin-1 analogues were designed and synthesized by one to three replacement of glycines with leucines at the hydrophilic face of chensinin-1 or rearrangement of some of the residues in its sequence. Circular dichroism spectroscopy showed that the analogues adopted α-helical-type conformations in 50% trifluoroethanol/water but adopted β-strand-type conformations in 30 mmol l−1 sodium dodecyl sulphate. The anti-microbial activities of the peptides against Gram-positive bacteria increased 5- to 30-fold, and these increases paralleled the increases in the peptides' hydrophobicities. Their haemolytic activities also increased. Amphipathicities had little influence on the bactericidal activity of chensinin-1. All peptides caused leakage of calcein entrapped in negatively charged liposomes although with different efficiencies. The peptides did not induce leakage of calcein from uncharged liposomes. Conclusions Peptide adopted an aperiodic structure can improve the anti-microbial potency by increasing peptide hydrophobicity. Its target is bacteria plasma membrane. Significance and Impact of the Study Chensinin-1 can act as a new lead molecule for the study of AMPs with atypical structures. [ABSTRACT FROM AUTHOR]

Abstract: Amphipathic peptides with unusual cellular translocation properties have been used as carriers of different biomolecules. However, the parameters which control the delivery efficiency of a particular cargo by a peptide and the selectivity of cargo delivery are not very well understood. In this work, we have used the known cell penetrating peptide pVEC (derived from VE-cadherin) and systematically changed its amphipathicity (from primary to secondary) as well as the total charge and studied whether these changes influence the plasmid DNA condensation ability, cellular uptake of the peptide–DNA complexes and in turn the efficiency of DNA delivery of the peptide. Our results show that although the efficiency of DNA delivery of pVEC is poor, modification of the same peptide to create a combination of nine arginines along with secondary amphipathicity improves its plasmid DNA delivery efficiency, particularly in presence of an endosomotropic agent like chloroquine. In addition, presence of histidines along with 9 arginines and secondary amphipathicity shows efficient DNA delivery with low toxicity even in absence of chloroquine in multiple cell lines. We attribute these enhancements in transfection efficiency to the differences in the mechanism of complex formation by the different variants of the parent peptide which in turn are related to the chemical nature of the peptide itself. These results exhibit the importance of understanding the physicochemical parameters of the carrier and complex in modulating gene delivery efficiency. Such studies can be helpful in improving peptide design for delivery of different cargo molecules. [Copyright &y& Elsevier]

The article examines the effects of perturbations imposed on the amphipatic moments of Gramicidin S (GS) cyclo-decapeptide analogues. Previous studies indicate that better antimicrobial selectivity is attained when the amphipatic moments of the analogues of GS-14 is perturbed. Structural studies of GS by molecular dynamics show a two-stranded antiparallel Β-sheets imposed by two Β-turns. The study concluded that the idea of perturbation on the amphipatic moment does not work for GS-10-0 analogues.

Abstract: Ring extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane amino acids resulted in a small set of compounds with varying amphipathic character. It was found that the amphipathicity of these compounds is correlated to their biological activity. Several bacterial strains including MRSA strains were shown to be killed by the novel peptides. The most potent antibacterial peptides are tetradecameric GS analogues containing six positives charges and two adamantane moieties. [Copyright &y& Elsevier]

The α-helix remains a focus of research because of its importance to protein folding and structure. Nevertheless, despite numerous empirical, computational, and theoretical studies, the fundamental structural properties governing their formation and stability are still unclear. We have examined the statistical occurrence of polar and apolar residue patterning in helical interiors in a large, non-redundant dataset, and compared these patterns with those found in other structural environments. While the familiar amphipathic distributions for both polar and apolar residues are evident, our analysis also finds significant differences between these distributions. Non-amphipathic signals can also be discerned within both distributions. Most interestingly, among various positional patterning, an analysis of immediate (i,i + 1) helical neighbours found: (i) clear neighbouring preferences, with high (low) occurrences of hydrophobics (hydrophilics) next to Gly, Pro, and short polar residues; (ii) high negative (positive) correlation between residue helical propensities and the degree of neighbouring hydrophobicity (hydrophilicity); and (iii) a preferred ordering among neighbours, implying an inherent helix directionality. Because (i,i + 1) helical pairs have limited side chain - side chain interactions, thermodynamic considerations cannot readily explain these observations, nor can evolutionary pressures that enhance tertiary interactions via amphipathicity, as this particular spacing does not segregate residues onto either the same or opposing helical faces. We suggest that the mechanism of helix formation may be partly responsible for these observations. In particular, the high negative correlation between residue helical propensities and neighbouring hydrophobicity suggests that hydrophobicity may play a more important role in helix formation than currently recognized. L’hélice α continue d’être l’objet de travaux de recherche compte tenu de son importance dans le repliement et la structure des protéines. Cependant, malgré de nombreuses études empiriques, informatiques et théoriques, les propriétés structurales fondamentales qui gouvernent leur formation et leur stabilité sont encore méconnues. Nous avons examiné l’occurrence statistique de résidus polaires et non polaires dans les patrons intérieurs des hélices dans une série de données exhaustives et non redondantes, et comparé ces patrons avec ceux trouvés dans d’autres environnements structuraux. Bien que la répartition amphipathique habituelle des résidus polaires et non polaires soit évidente, notre analyse révèle des différences considérables dans leur répartition respective. Des signaux non amphipathiques peuvent aussi être discernés à l’intérieur de ces deux types de répartition. Fait encore plus intéressant, parmi les différents patrons de position, une analyse des voisins adjacents (i,i +1) d’une hélice a révélé : (i) une préférence de voisinage claire, avec une forte occurrence de résidus hydrophobes (hydrophiles) à côté de résidus Gly, Pro et de courts résidus polaires; (ii) une forte corrélation négative (positive) entre la propension d’un résidu à former une hélice et le degré d’hydrophobicité du voisin; et (iii) un ordonnancement préférentiel parmi les voisins, impliquant une directivité inhérente de l’hélice. Puisque les paires hélicoïdales (i,i+1) possèdent des interactions entre les chaînes latérales, les considérations thermodynamiques ne peuvent véritablement expliquer ces observations; comme ne peuvent l’expliquer les pressions évolutives qui augmentent les interactions tertiaires en raison de l’amphipathie, car cet espacement particulier ne permet pas de ségréger les résidus sur les mêmes faces de l’hélice ou sur les faces opposées. Nous suggérons que le mécanisme de formation de l’hélice puisse être en partie responsable de ces observations. En particulier, la forte corrélation négative qui existe entre la propension d’un résidu à former une hélice et l’hydrophobicité adjacente suggère que l’hydrophobicité puisse jouer un rôle plus important dans la formation de l’hélice que ce qui est actuellement reconnu. [ABSTRACT FROM AUTHOR]