Hydrophobic Side Chains Research Articles

Insights into the Biomimetic Synthesis of 2D ZnO Nanomaterials through Peptoid Engineering.

Achieving predictable biomimetic crystallization using sequence-defined synthetic molecules in mild conditions represents a long-standing challenge in materials synthesis. Herein we report a peptoid-based approach for biomimetic control over the formation of nanostructured ZnO materials in ambient aqueous conditions. A series of two-dimensional (2D) ZnO nanomaterials have been successfully obtained using amphiphilic peptoids with different numbers, ratios, and patterns of various hydrophilic and hydrophobic side chains. By investigating the relationship between peptoid hydrophobicity and the thickness of the resultant ZnO nanomaterials, we found the critical role of peptoid hydrophobicity in the peptoid-controlled ZnO formation. Our results suggest that tuning the hydrophobicity of peptoids can be used to moderate peptoid-ZnO surface interactions, thus controlling the formation of ultrathin (<2.5 nm) 2D ZnO nanomaterials. The peptoid-controlled formation of ZnO nanomaterials was further investigated using ultrasmall-angle X-ray scattering (USAXS). Our work suggests a new approach to synthesizing 2D metal oxide nanomaterials using sequence-defined synthetic molecules.

Polypeptoids: Exploring the Power of Sequence Control in a Photoresist for Extreme‐Ultraviolet Lithography

AbstractA new type of a positive tone chemically amplified photoresist based on well‐defined, sequence‐controlled polypeptoids with ten repeat‐units are synthesized and their potential for extreme‐UV lithography (EUVL) is demonstrated, resulting in line‐space patterns of 70 nm pitch. The synthesized samples contain 4‐(ethyl) phenol (Eph) and propyne (Ppy) side chains, while their change in solubility upon exposure is induced by the deprotection of 4‐(ethyl) phenol side groups. The resist performance is evaluated using deep UV and extreme‐UV lithography. While all samples are developable in isopropyl alcohol, the content, and the sequence of hydrophobic alkyne side chains lead to a detectable change in solubility, dissolution rate, and resist performance.

Role of Hydrophobic Amino-Acid Side-Chains in the Narrow Selectivity Filter of the CFTR Chloride Channel Pore in Conductance and Selectivity.

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Structural analysis of CFTR has identified a narrow, hydrophobic region close to the extracellular end of the open channel pore that may function as a selectivity filter. The present study combines comprehensive mutagenesis of hydrophobic amino-acid side-chains within the selectivity filter with functional evaluation of channel Cl- conductance and anion selectivity. Among these hydrophobic amino-acids, one (F337) appears to play a dominant role in determining both conductance and selectivity. Anion selectivity appears to depend on both side-chain size and hydrophobicity at this position. In contrast, conductance is disrupted by all F337 mutations, suggesting that unique interactions between permeating Cl- ions and the native phenylalanine side-chain are important for conductance. Surprisingly, a positively charged lysine side-chain can be substituted for several hydrophobic residues within the selectivity filter (including F337) with only minor changes in pore function, arguing against a crucial role for overall hydrophobicity. These results suggest that localized interactions between permeating anions and amino-acid side-chains within the selectivity filter may be more important in determining pore functional properties than are global features such as overall hydrophobicity.

Side-Chain Labeling Strategy for Forming Self-Sorted Columnar Liquid Crystals from Binary Discotic Systems

The spontaneous formation of self-sorted columnar structures of electron-donating and accepting π-conjugated molecules is attractive for photoconducting and photovoltaic properties. However, the simple mixing of donor–acceptor discotic molecules usually results in the formation of mixed-stacked or alternating-stacked columns. As a new strategy for overcoming this problem, here, we report the “side-chain labeling” approach using binary discotic systems and realize the preferential formation of such self-sorted columnar structures in a thermodynamically stable phase. The demonstrated key strategy involves the use of hydrophobic and hydrophilic side chains. The prepared blend is composed of liquid crystalline phthalocyanine with branched alkyl chains (H2Pc) and perylenediimide (PDI) carrying alkyl chains at one side and triethyleneglycol (TEG) chains at the other side (PDIC12/TEG). To avoid the thermodynamically unfavorable contact among hydrophobic and hydrophilic chains, PDIC12/TEG self-assembles to stack up on top of each other and H2Pc as well, forming a homo-stacked pair of columns (self-sort). Importantly, H2Pc and PDIC12/TEG in the blend are macroscopically miscible and uniform, and mesoscopically segregated. The columnar liquid crystalline microdomains of H2Pc and PDIC12/TEG are homeotropically aligned in a glass sandwiched cell. The “labeling” strategy demonstrated here is potentially applicable to any binary discotic system and enables the preferential formation of self-sorted columnar structures.

Study on material and mechanical characteristics of silicone rubber shed of field-aged 110 kV composite insulators

Composite insulators have excellent performance and are more and more widely used in power grid. The performance of composite insulators with different service duration will decline in varying degrees, which could pose a threat to the safe operation of power grid. In order to investigate the influence of service duration and electric field strength on insulator shed performance, the sheds at different positions of insulators with different service duration are sampled. The hydrophobicity, material and mechanical properties of the samples are tested, and then the micro material properties tests are performed in terms of SEM, FTIR and XPS tests. Based on the above test results, the aging law and its mechanism of silicone rubber sheds are analyzed. The results reveal that the performance of insulator shed gradually decline with the increase of service life. The hydrophobicity and hardness of high-voltage end insulator are similar to that of middle section insulator, while other parameters are obviously different, indicating that the electric field can aggravate the aging. FTIR results show that the main chain and hydrophobic side chain of silicone rubber are destroyed, and the oxygen-containing groups increased, indicating that thermal oxygen aging occurred during operation. XPS and SEM results show that the crosslinking degree of silicone rubber increases and the porosity increases. The above changes in the microstructure of silicone rubber lead to the decline of insulator performance.

Elucidating Sequence-Assembly Relationships for Bilingual PNA Biopolymers.

Nucleic acids and proteins possess encoded "languages" that can be used for information storage or to direct function. However, each biopolymer is limited to encoding its respective "language." Using a peptide nucleic acid (PNA) scaffold, nucleobase and amino acid residues can be installed on a singular backbone, enabling a single biopolymer to encode both languages. Our laboratory previously reported the development of a "bilingual" PNA biopolymer that incorporates a sequence-specific nucleic acid code interspersed with hydrophobic (alanine) and hydrophilic (lysine) amino acid residues at defined positions to produce amphiphilic character. We observed the amphiphilic amino acid residues directing the biopolymer to undergo self-assembly into micelle-like structures, while the nucleic acid recognition was harnessed for disassembly. Herein, we report a series of bilingual PNA sequences having amino acid residues with varying lengths, functional group charges, hydrophobicities, and spacings to elucidate the effect of these parameters on micelle assembly and nucleic acid recognition. Negative charges in the hydrophilic block or increased bulkiness of the hydrophobic side chains led to assembly into similarly sized micelles; however, the negative charge additionally led to increased critical micelle concentration. Upon PNA sequence truncation to decrease the spacing between side chains, the biopolymers remained capable of self-assembling but formed smaller structures. Characterization of disassembly revealed that each variant retained sequence recognition capabilities and stimuli-responsive disassembly. Together, these data show that the amino acid and nucleic acid sequences of amphiphilic bilingual biopolymers can be customized to finely tune the assembly and disassembly properties, which has implications for applications such as the encapsulation and delivery of cargo for therapeutics.

Triosephosphate Isomerase: The Crippling Effect of the P168A/I172A Substitution at the Heart of an Enzyme Active Site.

The P168 and I172 side chains sit at the heart of the active site of triosephosphate isomerase (TIM) and play important roles in the catalysis of the isomerization reaction. The phosphodianion of substrate glyceraldehyde 3-phosphate (GAP) drives a conformational change at the TIM that creates a steric interaction with the P168 side chain that is relieved by the movement of P168 that carries the basic E167 side chain into a clamp that consists of the hydrophobic I172 and L232 side chains. The P168A/I172A substitution at TIM from Trypanosoma brucei brucei (TbbTIM) causes a large 120,000-fold decrease in kcat for isomerization of GAP that eliminates most of the difference in the reactivity of TIM compared to the small amine base quinuclidinone for deprotonation of catalyst-bound GAP. The I172A substitution causes a > 2-unit decrease in the pKa of the E167 carboxylic acid in a complex to the intermediate analog PGA, but the P168A substitution at the I172A variant has no further effect on this pKa. The P168A/I172A substitutions cause a 5-fold decrease in Km for the isomerization of GAP from a 0.9 kcal/mol stabilization of the substrate Michaelis complexes. The results show that the P168 and I172 side chains play a dual role in destabilizing the ground-state Michaelis complex to GAP and in promoting stabilization of the transition state for substrate isomerization. This is consistent with an important role for these side chains in an induced fit reaction mechanism [Richard, J. P. (2022) Enabling Role of Ligand-Driven Conformational Changes in Enzyme Evolution. Biochemistry 61, 1533-1542].

Alkali-resistant poly (vinyl benzyl chloride) based anion exchange membranes with outstanding flexibility and high hydroxide ion conductivity

Preparing AEMs with robust mechanical properties, high ionic conductivity and excellent chemical stability is challenging. Here, cross-linked/aggregated AEMs are prepared by incorporating hydrophilic Jeffamine cross-linkers and hydrophobic side chains into the rigid quaternized poly (vinyl benzyl chloride). Jeffamine's flexibility ensures high elongation at break of the cross-linked/aggregated membranes (125.0–199.8%). The hydrophobic side chain limits excessive water absorption and facilitates self-aggregation of hydrophilic and hydrophobic domains, enhancing tensile strength (5.08–7.40 Mpa in wet state) and improving ionic conductivity of the AEMs (73.8–110.4 mS cm−1 at 80 °C). Alkali-resistant PVB, restricted dimensionality, and ordered micro-phase separation morphology contribute to outstanding chemical stability of the AEMs. Degradation of both backbones and cations is <20% after treatment in 1 M NaOH solution at 80 °C for 30 days. Based on the membrane, a peak power density of 354.4 mW cm−2 at 60 °C is yielded.

Amyloid Aggregation Is Potently Slowed Down by Osmolytes Due to Compaction of Partially Folded State

Amyloid aggregation is a key process in amyloidoses and neurodegenerative diseases. Hydrophobicity is one of the major driving forces for this type of aggregation, as an increase in hydrophobicity generally correlates with aggregation susceptibility and rate. However, most experimental systems in vitro and prediction tools in silico neglect the contribution of protective osmolytes present in the cellular environment. Here, we assessed the role of hydrophobic mutations in amyloid aggregation in the presence of osmolytes. To achieve this goal, we used the model protein human muscle acylphosphatase (mAcP) and mutations to leucine that increased its hydrophobicity without affecting its thermodynamic stability. Osmolytes significantly slowed down the aggregation kinetics of the hydrophobic mutants, with an effect larger than that observed on the wild-type protein. The effect increased as the mutation site was closer to the middle of the protein sequence. We propose that the preferential exclusion of osmolytes from mutation-introduced hydrophobic side-chains quenches the aggregation potential of the ensemble of partially unfolded states of the protein by inducing its compaction and inhibiting its self-assembly with other proteins. Our results suggest that including the effect of the cellular environment in experimental setups and predictive softwares, for both mechanistic studies and drug design, is essential in order to obtain a more complete combination of the driving forces of amyloid aggregation.

Role of hydrophobic side chain in urea induced protein denaturation at interface

The molecular mechanism of denaturing ability of urea is still a subject of considerable debate due to two opposing mechanisms: direct and indirect. In the direct mechanism, urea directly disrupts hydrogen bonding and hydrophobic interactions within proteins. On the other hand, the indirect mechanism suggests that urea alters the properties of water and disrupts protein-protein interactions. Our aim is to unravel the denaturing mechanism of urea by studying its interaction with the side chain of octadecylphosphonic acid (ODPA)) as a mimicking surface of a protein. We employ vibrational sum frequency generation (VSFG) spectroscopy to examine the interaction between urea, the side chain of ODPA, and water molecules at the interface. Our findings suggest that urea interacts with the side chain of ODPA, effectively reducing the hydrophobic barriers provided by the long hydrophobic chain of the ODPA molecules for the water molecules at the interface. The interaction of the urea with the side chain of the ODPA molecules results in the alignment of water molecules, increasing their SFG intensity. Our findings indicate that the interaction of urea with the side chain plays a crucial role in governing the interaction between water and ODPA molecules. These outcomes help us understand the side chain's role in urea-induced protein denaturation at the interface.

Asymmetric Synthesis of Functionalizable Type II β-Turn-Inducing α-Amino Acid Building Blocks.

Peptidomimetics are emerging as a promising class of potent and selective therapeutics. Among the current approaches to these compounds, the utilization of constrained lactams is a key element in enforcing the active peptide conformation, and the development of efficient and stereocontrolled methods for generating such lactam building blocks is an important objective. Current methods typically rely on the elaboration of existing α-amino acids, and in so doing, the side chain is sacrificed during the ring-forming process. We report a new asymmetric approach to lactam-constrained α-amino acid building blocks bearing a range of polar and hydrophobic side chains. The chemistry is amenable to rapidly generating di- and tripeptides, and the potential for these lactams to stabilize type II β-turns is demonstrated in the synthesis of the melanocyte-inhibiting factor peptidomimetic.

Fabrication of UV-curable waterborne polyurethane coatings with self-cleaning, anti-graffiti performance, and corrosion resistance

A novel UV-curable anti-smudge coating based on waterborne polyurethane (WPU) was constructed by using polydimethylsiloxane (PDMS) as hydrophobic material and pentaerythritol triacrylate (PETA) as UV-curable cross-linking agent. At the same time, the effect of PDMS loading and the cross-linking density on the transparency, hydrophobicity, as well as graffiti resistance of the coating, were investigated. Due to the high cross-linking density, the obtained coating possessed desirable optical transparency. The synergistic effect of hydrophobic side chains and dense cross-linking imparts the coating favorable repellency to pollutant liquids such as water, coffee, muddy water, ink, hexadecane, ethanol, fingerprint liquid and others. The coating showed good anti-graffiti properties on a variety of substrates, including glass, tinplate, ceramics, wood, and paper sheet. In addition, aside from protecting the substrate against strong acid, alkali, and salt solutions, the coatings remained stain resistant despite being folded and curled. This study provides a new strategy for the design of WPU UV-curable anti-smudge coatings.

Coarse-Grained Molecular Simulation of Bolapolyphiles with a Multident Lateral Chain: Formation and Structural Analysis of Cubic Network Phases.

Bolapolyphiles constitute a versatile class of materials with a demonstrated potential to form a wide variety of complex ordered mesophases. In particular, cubic network phases (like the gyroid, primitive, and diamond phases) have been a target of many studies for their ability to create percolating 3D nanosized channels. In this study, molecular simulations are used to explore the phase behavior of bolapolyphiles containing a rigid rodlike core, associating hydrophilic core ends and a hydrophobic side chain with a multident architecture, i.e., where the branching pattern can vary from bident (two branches) to hexadent (six branches). Upon network phase formation, its skeleton is made up of "nodes" populated by the core ends and "struts" populated by the cores. It is shown that, by varying the side chain length, branching pattern, and attachment point to the core, one can alter the crowding around the cores and hence tune the nodal size and nodal valence (i.e., number of connecting struts) which lead to different types of network morphologies. For example, for a fixed total side chain length, having more branches generates a stronger crowding around the molecular core, driving them to form bundlelike domains with curvier interfaces that result in thinner struts. Also, attaching the lateral chain closer to one core end breaks the symmetry between the environments around the two core ends, leading to networks with bimodal nodal sizes. Importantly, since the characterization of (ordered or partially ordered) network phases is challenging given the potential incompatibilities between the simulation box size with the structure's space group periodic symmetry and the effect of morphological defects, a detailed framework is presented to analyze and fully characterize the unit cell parameters and structure factor of such systems.

Radical-Mediated Covalent Azidylation of Hydrophobic Microdomains in Water-Soluble Proteins.

Hydrophobic microdomains, also known as hydrophobic patches, are essential for many important biological functions of water-soluble proteins. These include ligand or substrate binding, protein-protein interactions, proper folding after translation, and aggregation during denaturation. Unlike transmembrane domains, which are easily recognized from stretches of contiguous hydrophobic sidechains in amino acids via primary protein sequence, these three-dimensional hydrophobic patches cannot be easily predicted. The lack of experimental strategies for directly determining their locations hinders further understanding of their structure and function. Here, we posit that the small triatomic anion N3- (azide) is attracted to these patches and, in the presence of an oxidant, forms a radical that covalently modifies C-H bonds of nearby amino acids. Using two model proteins (BSA and lysozyme) and a cell-free lysate from the model higher plant Arabidopsis thaliana, we find that radical-mediated covalent azidylation occurs within buried catalytic active sites and ligand binding sites and exhibits similar behavior to established hydrophobic probes. The results herein suggest a model in which the azido radical is acting as an "affinity reagent" for nonaqueous three-dimensional protein microenvironments and is consistent with both the nonlocalized electron density of the azide moiety and the known high reactivity of azido radicals widely used in organic chemistry syntheses. We propose that the azido radical is a facile means of identifying hydrophobic microenvironments in soluble proteins and, in addition, provides a simple new method for attaching chemical handles to proteins without the need for genetic manipulation or specialized reagents.

Morphological Transitions in Solutions of Macromolecules with Solvophilic Backbone and Orientationally Mobile Solvophobic Side Groups

A theoretical model describing the self-assembly in dilute solutions of amphiphilic macromolecules containing the backbone built of the solvophilic units (the P groups) and the solvophobic side chains (the H groups) possessing orientational mobility relative to the backbone units has been elaborated. In the framework of strong segregation limit (The size of the insoluble regions of the formed micelles is on the order of the hydrophobic side chains), state diagrams of the solution have been calculated with and without accounting for the orientational entropy contribution of the side groups to the total free energy of the solution at different thermodynamic qualities of solvent for the macromolecules and the grafting density of the H groups; the regions of stability of spherical and cylindrical micelles as well as planar bilayers (vesicles) have been revealed. It has been found that the contribution of the orientational entropy significantly affects the view of the state diagrams. In the case of considering the orientational mobility, the conditions of the cylindrical micelle stability are very sensitive to the change in the grafting density of the side groups. This sensitivity can be the reason why the formation of long cylindrical (wormlike) micelles is not observed in experiments and computer simulations. As earlier demonstrated at a qualitative level, the orientational mobility of the side groups can lead to the emergence of the orientation-induced attraction between the polymer micelles (A. I. Buglakov, D. E. Larin, and V. V. Vasilevskaya, Polymer 232, 124160 (2021)). In this study, exact analytical calculations of the energy of orientation-induced attraction for the case of the interaction between two planar bilayer micelles has been performed. At distances being of the order of the size of the side H group, the orientation-induced attraction forces are much stronger than the van der Waals forces and, hence, the orientation-induced attraction can be decisive in the formation of large aggregates observed in experiments.

Thermodynamic Basis for the Stabilization of Helical Peptoids by Chiral Sidechains.

Peptoids are a class of highly customizable biomimetic foldamers that retain properties from both proteins and polymers. It has been shown that peptoids can adopt peptide-like secondary structures through the careful selection of sidechain chemistries, but the underlying conformational landscapes that drive these assemblies at the molecular level remain poorly understood. Given the high flexibility of the peptoid backbone, it is essential that methods applied to study peptoid secondary structure formation possess the requisite sensitivity to discriminate between structurally similar yet energetically distinct microstates. In this work, a generalizable simulation scheme is used to robustly sample the complex folding landscape of various 12mer polypeptoids, resulting in a predictive model that links sidechain chemistry with preferential assembly into one of 12 accessible backbone motifs. Using a variant of the metadynamics sampling method, four peptoid dodecamers are simulated in water: sarcosine, N-(1-phenylmethyl)glycine (Npm), (S)-N-(1-phenylethyl)glycine (Nspe), and (R)-N-(1-phenylethyl)glycine (Nrpe)─to determine the underlying entropic and energetic impacts of hydrophobic and chiral peptoid sidechains on secondary structure formation. Our results indicate that the driving forces to assemble Nrpe and Nspe sequences into polyproline type-I helices in water are found to be enthalpically driven, with small benefits from an entropic gain for isomerization and steric strain due to the presence of the chiral center. The minor entropic gains from bulky chiral sidechains in Nrpe- and Nspe-containing peptoids can be explained through increased configurational entropy in the cis state. However, overall assembly into a helix is found to be overall entropically unfavorable. These results highlight the importance of considering the many various competing interactions in the rational design of peptoid secondary structure building blocks.

Origins of Conformational Heterogeneity in Peptoid Helices Formed by Chiral N-1-Phenylethyl Sidechains.

N-substituted glycines (polypeptoids) containing chiral hydrophobic sidechains are known to fold into biomimetic alpha helices. These helix formers often produce conformationally heterogeneous structures and are difficult to characterize at a sub-nanometer resolution. Previously, peptoid N-1-phenylethyl (S)-enantiomer sidechains (Nspe) were inferred from various experiments to form right-handed helices and (R)-enantiomers (Nrpe), left-handed helices. Prior computational work for N(s/r)pe oligomers has struggled to reproduce this trend. Herein, quantum mechanics calculations and molecular dynamics simulations are used to understand the origins of this discrepancy. Results from DFT and molecular mechanics calculations on a variety of Nspe and Nrpe oligomers as a function of chain length are in agreement, showing that Nspe and Nrpe prefer left- and right-handed helices, respectively. Additional metadynamics simulations are used to study Nrpe and Nspe oligomers folding in water. These results show that the free-energy driving forces for assembly into a helical backbone configuration are very small (within ∼kBT). Lastly, we compare DFT calculations for other experimentally characterized peptoid sidechains, N(r/s)sb, N(r/s)tbe, and N(r/s)npe. In this analysis, we show that peptoid sidechains determined to be more robust experimentally (tbe and npe) have helical preferences opposite the trend seen in less robust assemblies formed by N(r/s)pe and N(r/s)sb chemistries. The more robust tbe and nnpe favor the (S)-enantiomer to right-handed and the (R)-enantiomers to left-handed helices.

A photocured bio-based shape memory thermoplastics for reversible wet adhesion

Development of reversible wet or underwater adhesives remains a grand challenge, because weakened intermolecular interactions by water molecules or/and low effective contact area cause poor interface to the wet surfaces, which significantly decreases adhesive strength. Herein, a new photocured, bio-based shape memory polymer (SMP) that shows both chemical and structural wet adhesion to various types of surfaces is developed. The SMP is polymerized from three monomers to form linear polymer chains dangled with hydrophobic side chains. The hydrogen acceptor and donor groups in the chains form hydrogen bonding with the surfaces, which is protected by the hydrophobic chains in the interface. The SMP shows tunable phase transition temperature (Tg) of 17–38 °C. In a rubbery state above Tg, the adhesive forms conformable contact with the targeted surfaces. Below Tg, a transition to a glassy state locks the conformed shapes to largely increase the effective contact area. As a result, the adhesive exhibits long-term underwater adhesion of >15 days with the best adhesion strength of ∼0.9 MPa. Its applications in leak repair, underwater on-skin sensors were demonstrated. This new, general strategy would pave avenues to designing bio-based, long-lasting, and reversible adhesives from renewable feedstocks for widespread applications.

A non-cationic crosslinking strategy to improve the performance of anion exchange membranes based on poly(aryl piperidinium) for fuel cells

As a backbone with ether-free for anion exchange membranes (AEMs) with good alkali stability, poly(aryl-co-aryl piperidine) (c-PAP) has received much attention in the development of polyelectrolytes. More importantly, the trade-off between high conductivity and stability has been a thorny issue for researchers in the study of AEMs. Typically, non-cationic crosslinked membranes have lower water absorption and swelling rates compared to multi-cationic crosslinked membranes, resulting in better dimensional stability of the membrane. Here, we designed a non-cationic crosslinked AEMs based on poly(p-terphenyl-co-1,2-diphenylethane piperidinium) (PDTP). The experimental results show that the combination of hydrophobic crosslinking and side chain induction results in excellent conductivity and alkali resistance of the membranes. The crosslinked membranes reached an OH- conductivity of 104.61 mS cm−1 and a swelling rate of less than 15 % at 80 °C. In addition, the length of the hydrophobic crosslinker was varied to explore its effect on the membrane properties. The PDTP-BMP-6 C membrane (C=6 in crosslinker) shows the most excellent overall performance among them. The conductivity was retained at 86.5 % after immersion in 2 M NaOH at 80 °C for 720 h, and the peak power density reached 214 mW cm−2.

Aryl Crown Ethers Based on d‐Glucose Scaffold – Highly Selective Receptors of Amino Acid Ester Hydrochlorides

AbstractAmino acids are important biomolecules with a broad scope of applications in chemical and biological sciences. Their functions and properties depend on their absolute configuration. Therefore, methods for chiral recognition and separation of amino acids are highly sought after. For the purposes of diagnostic and medicinal applications chiral recognition of amino acids in water is particularly relevant. However synthetic receptors for enantioselective binding of amino acids in aqueous media are rare. Recently we reported a d‐glucose‐based crown ether for chiral recognition of amino acid esters in water. We achieved enantioselectivities towards amino acids with hydrophobic sidechains which were among the highest ever reported for a small molecule receptor. The binding affinities were however moderate. Herein we disclose analogs of that receptor, containing aryl functionalities in the crown ether fragment. The new receptors show considerably improved binding affinities for amino acid ester hydrochlorides in water, while retaining high enantio‐ or chemoselectivities.