Hydrophobic Side Chains Research Articles

β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

Hydrophobically Modified Polyacrylamide Incorporating Both Hydrophilic and Hydrophobic Units: Enhanced Printability and Stability in Aqueous Ink.

For this research, three hydrophobically modified polyacrylamides, HPAAB, HPAAF, and HPAAS, with multiple hydrophobic monomers were designed, synthesized, and used as thickeners in aqueous ink for digital ink-jet printing. The structures were characterized by Fourier transform infrared (FTIR) analysis and nuclear magnetic resonance (NMR) spectroscopy. The viscosity-average molecular weight was determined by intrinsic viscosity determination and was adjusted according to hydrophobic content. The critical association concentration (CAC) of polymers was measured simultaneously using the apparent viscosity method and the fluorescence spectrum. The formation of a network structure and the mechanism of hydrophobic association are visualized dynamically with a scanning electron microscope (SEM) at different concentrations. Under the same conditions, HPAAB exhibited excellent thickening ability across different pH levels, temperatures, and shear rates, which is caused by the longer hydrophobic side chain and the stronger hydrophobic effect of the behenyl polyoxyethylene ether methacrylate (BEM) group. Furthermore, an aqueous ink using HPAAB as a thickener displays significant printability and stability, functioning much better than a corresponding aqueous ink that uses a commercial thickener. This is the first example of a hydrophobic associating polyacrylamide, incorporating both hydrophilic and hydrophobic units within a single hydrophobic chain, thereby serving as an efficient thickener for aqueous ink.

Decisive Effect of Hydrophobic Rigid-Flexible Coupled Side Chains of Polycarbazoles on the Performance of Anion Exchange Membranes for Fuel Cells

Decisive Effect of Hydrophobic Rigid-Flexible Coupled Side Chains of Polycarbazoles on the Performance of Anion Exchange Membranes for Fuel Cells

Behavior of Trapped Molecules in Lantern-Like Carcerand Superphanes.

Superphanes are a group of organic molecules from the cyclophane family. They are characterized by the presence of two parallel benzene rings joined together by six bridges. If these bridges are sufficiently long, the superphane cavity can be large enough to trap small molecules or ions. Using ab initio (time scale of 80 ps) and classical (up to 200 ns) molecular dynamics (MD) methods, we study the behavior of five fundamental molecules (M = H2O, NH3, HF, HCN, MeOH) encapsulated inside the experimentally reported lantern-like superphane and its two derivatives featuring slightly modified side bridges. The main focus is studying the dynamics of hydrogen bonds between the trapped M molecule and the imino nitrogen atoms of the side chains of the host superphane. The length of the N···H hydrogen bond increases in the following order: HF < HCN < H2O < MeOH < NH3. The mobility of the trapped molecule and its preferred position inside the superphane cage depend not only on the type of this molecule but also largely on the in/out conformational arrangement of the imino nitrogens in the side chains of the superphane. Their inward-pointing positions allow the formation of strong N···H hydrogen bonds. For this reason, these nitrogens are the preferred sites of interaction. The mobility of the molecules and their residence times on each side of the superphane have been explained by referring to the symmetry and conformation of the given superphane cage. All force field MD simulations have shown that the encapsulated molecule remained inside the superphane cage for 200 ns without any escape event to the outside. Moreover, our simulations based on some endohedral complexes in the water box also showed no exchange event. Thus, the superphanes we study are true carcerand molecules. We attribute this property to the hydrophobic side chains and their pinwheel arrangement, which makes the side walls of the studied superphanes fairly impenetrable to small molecules.

The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition

Human histone deacetylase 4 (HDAC4) belongs to class IIa of the zinc-dependent histone deacetylases. HDAC4 is an established target for various indication areas, in particular Huntington’s disease, heart failure and cancer. To reduce unwanted side effects, it is advantageous to develop isozyme-selective inhibitors, which poses a major challenge due to the highly conserved active centers of the HDAC family.According to current knowledge it is assumed that H976 in HDAC4wt occurs exclusively in the out-conformation and thus the selective foot pocket is constitutively open. In contrast, the side chain of the corresponding tyrosine in HDAC4H976Y adopts the in-conformation, and is thus able to stabilize the intermediate state of the deacetylation reaction and block access to the foot pocket.In this study, we provide evidence that a dynamic equilibrium exists between the in- and out-conformation in HDAC4wt. The binding of selective HDAC4 inhibitors that address the foot pocket can be enhanced in HDAC4 variants with mainly small, but also medium hydrophobic or polar side chains. We attribute this to the fact that these side chains are preferentially present in the out-conformation.Therefore, we propose HDAC4H976A and other HDAC4 variants as promising tools to find and enrich HDAC4-selective foot pocket binders in screening campaigns that might have been overlooked in conventional screens with HDAC4wt.

Hydrophobic assembly of molecular catalysts at the gas-liquid-solid interface drives highly selective CO2 electromethanation.

Molecular catalysts offer tunable active and peripheral sites, rendering them ideal model systems to explore fundamental concepts in catalysis. However, hydrophobic designs are often regarded as detrimental for dissolution in aqueous electrolytes. Here we show that established cobalt terpyridine catalysts modified with hydrophobic perfluorinated alkyl side chains can assemble at the gas-liquid-solid interfaces on a gas diffusion electrode. We find that the self-assembly of these perfluorinated units on the electrode surface results in a catalytic system selective for electrochemical CO2 reduction to CH4, whereas every other cobalt terpyridine catalyst reported previously was only selective for CO or formate. Mechanistic investigations suggest that the pyridine units function as proton shuttles that deliver protons to the dynamic hydrophobic pocket in which CO2 reduction takes place. Finally, integration with fluorinated carbon nanotubes as a hydrophobic conductive scaffold leads to a Faradaic efficiency for CH4 production above 80% at rates above 10 mA cm-2-impressive activities for a molecular electrocatalytic system.

Inhibition of Aβ16-22 Aggregation by [TEA]+[Ms]- Follows Weakening of the Hydrophobic Core and Sequestration of Peptides in Ionic Liquid Nanodomains.

We developed a coarse-grained model for the protic ionic liquid, triethylammonium mesylate ([TEA]+[Ms]-), to characterize its inhibitory effects on amyloid aggregation using the K16LVFFAE22 fragment of the amyloid-β (Aβ16-22) as a model amyloidogenic peptide. In agreement with previous experiments, coarse-grained molecular dynamics simulations showed that increasing concentrations of [TEA]+[Ms]- in aqueous media led to increasingly small Aβ16-22 aggregates with low beta-sheet contents. The cause of [TEA]+[Ms]-'s inhibition of peptide aggregation was found to be a result of two interrelated effects. At a local scale, the enrichment of interactions between [TEA]+ cations and hydrophobic phenylalanine side chains weakened the hydrophobic cores of amyloid aggregates, resulting in poorly ordered structures. At a global level, peptides tended to localize at the interfaces of IL-rich nanostructures with water. At high IL concentrations, when the IL-water interface was large or fragmented, Aβ16-22 peptides were dispersed in the simulation cell, sometimes sequestered at unaggregated monomeric states. Together, these phenomena underlie [TEA]+[Ms]-'s inhibition of amyloid aggregation. This work addresses the critical lack of knowledge on the mechanisms of protein-ionic liquid interactions and may have broader implications for industrial applications.

Interfacial Stabilization of Organic Electrochemical Transistors Conferred Using Polythiophene-Based Conjugated Block Copolymers with a Hydrophobic Coil Design.

The recent interest in developing low-cost, biocompatible, and lightweight bioelectronic devices has focused on organic electrochemical transistors (OECTs), which have the potential to fulfill these requirements. In this study, three types of poly(3-hexylthiophene) (P3HT)-based block copolymers (BCPs) incorporating different insulating blocks (poly(nbutyl acrylate) (PBA), polystyrene, and poly(ethylene oxide) (PEO)) were synthesized for application in OECTs. The morphological, crystallographic, and electrochemical properties of these BCPs are systematically investigated. Accordingly, P3HT-b-PBA demonstrates superior performance in the KCl-based aqueous electrolyte, with a higher product of mobility and capacitance (μC*) at 170 F s-1 cm-1 V-1 than that of the P3HT homopolymer at 58 F s-1 cm-1 V-1. P3HT-b-PBA exhibits better stability over 50 ON/OFF switching cycles than do other BCPs and P3HT homopolymers. With regard to the performance in the KPF6-based aqueous electrolyte, P3HT-b-PBA outperforms with a higher μC* of 9.2 F s-1 cm-1 V-1 than that of 8.6 F s-1 cm-1 V-1 observed from P3HT. Notably, both polymers exhibited almost no decay in device performance over 110 ON/OFF switching cycles. The strongly different performance of polymers in these two electrolytes is due to the side chain's hydrophobicity and interdigitated lamellar structures, thereby retarding the doping kinetics of the highly hydrated Cl- ions compared with the slightly hydrated PF6- ions. Concerning the improved performance of P3HT-b-PBA, this is attributed to its soft and hydrophobic backbone. Our morphological and crystallographic analyses reveal that P3HT-b-PBA experiences minimal structural disorder when swelled by the electrolyte, maintaining its original structure better than the P3HT homopolymer and the hydrophilic BCP of P3HT-b-PEO. The hydrophobic nature of P3HT-b-PBA contributes to the stability of its backbone structure, ensuring enhanced capacitance during the operation of the OECT operation. These findings provide reassurance about the stability and performance of P3HT-b-PBA in the field of OECT applications. In summary, this study represents the first exploration of P3HT-based BCPs for OECT applications and investigates their structure-performance relationships in mixed ionic-electronic conductors.

Sensitive Coatings Based on Molecular-Imprinted Polymers for Triazine Pesticides' Detection.

Triazine pesticide (atrazine and its derivatives) detection sensors have been developed to thoroughly check for the presence of these chemicals and ultimately prevent their exposure to humans. Sensitive coatings were designed by utilizing molecular imprinting technology, which aims to create artificial receptors for the detection of chlorotriazine pesticides with gravimetric transducers. Initially, imprinted polymers were developed, using acrylate and methacrylate monomers containing hydrophilic and hydrophobic side chains, specifically for atrazine, which shares a basic heterocyclic triazine structure with its structural analogs. By adjusting the ratio of the acid to the cross-linker and introducing acrylate ester as a copolymer, optimal non-covalent interactions were achieved with the hydrophobic core of triazine molecules and their amino groups. A maximum sensor response of 546 Hz (frequency shift/layer height equal to 87.36) was observed for a sensitive coating composed of 46% methacrylic acid and 54% ethylene glycol dimethacrylate, with a demonstrated layer height of 250 nm (6.25 kHz). The molecularly imprinted copolymer demonstrated fully reversible sensor responses, not only for atrazine but also for its metabolites, like des-ethyl atrazine, and structural analogs, such as propazine and terbuthylazine. The efficiency of modified molecularly imprinted polymers for targeted analytes was tested by combining them with a universally applicable quartz crystal microbalance transducer. The stable selectivity pattern of the developed sensor provides an excellent basis for a pattern recognition procedure.

Micellar structure of decenyl succinic anhydride modified pullulan with degree of substitution dependence in aqueous solution

A broad distribution pullulan (PUL) sample was hydrophobically modified by a relative longer decenyl succinic anhydride (DCSA) side chains with seven different degree of substitution (DS) to obtain the PUL-DCSA. The micellar structure of PUL-DCSA with DS dependence was investigated by pyrene-probe fluorescence and small-angle X-ray scattering (SAXS) in 0.05 M aqueous NaCl. While PUL-DCSA with DS > 0.26, both the SAXS and fluorescence results can be explained by the flower necklace model, when DS < 0.26, PUL-DCSA forms the loose flower necklace model. Moreover, the micellar structure of PUL-DCSA characterized by SAXS and fluorescence was different from that of the PUL-bearing shorter alkyl (octenyl or nonenyl) chains. The smaller chain stiffness qFN and larger number of monomer (glucose residues) per unit flower micelle N0u of PUL-DCSA, mainly due to the difference in the different hydrophobic alkyl side chains. This research will provide a theoretical guidance for designing biomedical materials with appropriate scale and characteristic functions in drug delivery system.

Uncovering the membrane and pore formation mechanisms of the lysozyme membrane made via the amyloid-like assembly

Biomimetic protein membranes have attracted increasing interests because of their distinctive separation properties in the membrane field. Low-cost and stable protein lysozyme has been intensively invetigated to fabricate high-performance sepration membranes via a facile and scalable method of amyloid-like assembly. However, the pore formation mechnism of the lysozyme membrane remains unclear. Herein, the lysozyme membranes were fabricated and the membrane formation mechnism and separation properties were investigated experimentally. Molecular dynamics simulation (MDS) was also employed to reveal the pore formation mechanism of the lysozyme membrane. The fabricated lysozyme membrane achieved a stable high water permeance of 10.2 L m−2 h−1 bar−1, as well as a relatively high separation factor (9.5) towards antibiotic and sodium chloride. MDS results found that the membrane pore size is governed by the amino acid compositions and is negatively dependent on the intermolecular forces among amino acids around the pores. Selective pores with 0.54 nm in diameter are primarily formed by these amino acids including alanine (35 %), aspartic acid (25 %), arginine (15 %), phenylalanine (11 %), and lysine (7 %), in which half of them have hydrophobic side chains with no charge, and another half have hydrophilic side chains with balanced charges. This work may stimulate the development of highly permeable and selective protein membranes by carefully engineering their amino acid compositions with optimal charges and hydrophobicity for generation of numerous selective pores.

De Novo Design and Characterization of Amphiphilic Peptides with Basic Side Chains for Tailored Interfacial Chemistries.

Lysine-leucine (LK) peptides have been used as model systems and platforms for 2D material design for decades. LK peptides are amphiphilic sequences designed to bind and fold at hydrophobic surfaces through hydrophobic leucine side chains and hydrophilic lysine side chains extending into the aqueous subphase. The hydrophobic periodicity of the sequence dictates the secondary structure at the interface. This robust design makes them ideal candidates for controlling interfacial chemistry. This study presents the de novo design and characterization of two novel peptides: LRα14 and LHα14, which substitute lysine with arginine and histidine, respectively, in the helical LKα14 sequence. This modification is intended to expand the LK peptide platform to a new basic interfacial chemistry. We explore the stability of the new LRα14 and LHα14 designs with respect to changes in pH and salt concentration in bulk solution and at the interface using circular dichroism (UV-CD) and vibrational sum-frequency generation spectroscopy, respectively. Notably, the structural stability of the peptides remains unaffected across a wide range of pH and ionic strength values. At the same time, the variation of side-chain chemistry leads to a wide spectrum of interfacial water structures. By extension of the LK platform to include arginine and histidine, this study broadens the toolbox for designing tailored interfacial chemistries with applications in material and biomedical sciences.

NMR Dynamic View of the Stabilization of the WW4 Domain by Neutral NaCl and Kosmotropic Na2SO4 and NaH2PO4.

The Hofmeister series categorizes ions based on their effects on protein stability, yet the microscopic mechanism remains a mystery. In this series, NaCl is neutral, Na2SO4 and Na2HPO4 are kosmotropic, while GdmCl and NaSCN are chaotropic. This study employs CD and NMR to investigate the effects of NaCl, Na2SO4, and Na2HPO4 on the conformation, stability, binding, and backbone dynamics (ps-ns and µs-ms time scales) of the WW4 domain with a high stability and accessible side chains at concentrations ≤ 200 mM. The results indicated that none of the three salts altered the conformation of WW4 or showed significant binding to the four aliphatic hydrophobic side chains. NaCl had no effect on its thermal stability, while Na2SO4 and Na2HPO4 enhanced the stability by ~5 °C. Interestingly, NaCl only weakly interacted with the Arg27 amide proton, whereas Na2SO4 bound to Arg27 and Phe31 amide protons with Kd of 32.7 and 41.6 mM, respectively. Na2HPO4, however, bound in a non-saturable manner to Trp9, His24, and Asn36 amide protons. While the three salts had negligible effects on ps-ns backbone dynamics, NaCl and Na2SO4 displayed no effect while Na2HPO4 significantly increased the µs-ms backbone dynamics. These findings, combined with our recent results with GdmCl and NaSCN, suggest a microscopic mechanism for the Hofmeister series. Additionally, the data revealed a lack of simple correlation between thermodynamic stability and backbone dynamics, most likely due to enthalpy-entropy compensation. Our study rationalizes the selection of chloride and phosphate as the primary anions in extracellular and intracellular spaces, as well as polyphosphate as a primitive chaperone in certain single-cell organisms.

Versatile Underwater Pressure Sensitive Adhesive: UV Curing Synthesis and Substrate-Independent Adhesion.

The demand for underwater pressure sensitive adhesives (PSAs) is rapidly increasing in fields such as underwater engineering and biomedicine. However, the achievement of underwater adhesion of PSAs remains a challenge because of the hydration layer that hinders the interaction between the adhesive and the substrate. Herein, a new type of underwater PSA was synthesized by the copolymerization of hydrophobic unsaturated poly(1,2-butylene oxide) (UPBO) and hydrophilic itaconic acid monomers using solvent-free ultraviolet curing. The PSA has demonstrated substrate-independent underwater adhesion strengths ranging from 108 to 141 kPa on both hydrophilic (glass, wood, steel) and hydrophobic (PET, PMMA, PTFE) substrates. The underwater adhesion performance of PSA remains stable during 30 adhesion-detachment cycles and incubation in water for 20 days. Notably, PSA shows cytocompatibility, antimicrobial, and degradable properties and can be used for rapid hemostasis of skin wounds. Experimental characterizations confirm that the process of underwater adhesion is achieved by hydrophobic alkyl side chains of the PBO chain segments, which repel water at the adhesive-substrate interface. This study should provide both practical and facile design strategies for multifunctional underwater PSAs that can be used in a variety of applications.

Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia

Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi’s.

Saturation Mutagenesis and Molecular Modeling: The Impact of Methionine 182 Substitutions on the Stability of β-Lactamase TEM-1.

Serine β-lactamase TEM-1 is the first β-lactamase discovered and is still common in Gram-negative pathogens resistant to β-lactam antibiotics. It hydrolyzes penicillins and cephalosporins of early generations. Some of the emerging TEM-1 variants with one or several amino acid substitutions have even broader substrate specificity and resistance to known covalent inhibitors. Key amino acid substitutions affect catalytic properties of the enzyme, and secondary mutations accompany them. The occurrence of the secondary mutation M182T, called a "global suppressor", has almost doubled over the last decade. Therefore, we performed saturating mutagenesis at position 182 of TEM-1 to determine the influence of this single amino acid substitution on the catalytic properties, thermal stability, and ability for thermoreactivation. Steady-state parameters for penicillin, cephalothin, and ceftazidime are similar for all TEM-1 M182X variants, whereas melting temperature and ability to reactivate after incubation at a higher temperature vary significantly. The effects are multidirectional and depend on the particular amino acid at position 182. The M182E variant of β-lactamase TEM-1 demonstrates the highest residual enzymatic activity, which is 1.5 times higher than for the wild-type enzyme. The 3D structure of the side chain of residue 182 is of particular importance as observed from the comparison of the M182I and M182L variants of TEM-1. Both of these amino acid residues have hydrophobic side chains of similar size, but their residual activity differs by three-fold. Molecular dynamic simulations add a mechanistic explanation for this phenomenon. The important structural element is the V159-R65-E177 triad that exists due to both electrostatic and hydrophobic interactions. Amino acid substitutions that disturb this triad lead to a decrease in the ability of the β-lactamase to be reactivated.

A classic antibiotic reimagined: Rationally designed bacitracin variants exhibit potent activity against vancomycin-resistant pathogens

Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.

NMR Dynamic View of the Destabilization of WW4 Domain by Chaotropic GdmCl and NaSCN.

GdmCl and NaSCN are two strong chaotropic salts commonly used in protein folding and stability studies, but their microscopic mechanisms remain enigmatic. Here, by CD and NMR, we investigated their effects on conformations, stability, binding and backbone dynamics on ps-ns and µs-ms time scales of a 39-residue but well-folded WW4 domain at salt concentrations ≤200 mM. Up to 200 mM, both denaturants did not alter the tertiary packing of WW4, but GdmCl exerted more severe destabilization than NaSCN. Intriguingly, GdmCl had only weak binding to amide protons, while NaSCN showed extensive binding to both hydrophobic side chains and amide protons. Neither denaturant significantly affected the overall ps-ns backbone dynamics, but they distinctively altered µs-ms backbone dynamics. This study unveils that GdmCl and NaSCN destabilize a protein before the global unfolding occurs with differential binding properties and µs-ms backbone dynamics, implying the absence of a simple correlation between thermodynamic stability and backbone dynamics of WW4 at both ps-ns and µs-ms time scales.

Theoretical simulation of OH− transport in poly(arylene indole piperidinium) anion exchange membranes: Effect of side-chain chemical structure

The introduction of long side chains into anion exchange membranes (AEMs) is a common strategy for improving OH− transport. However, the effect of different chemical structures of side-chain on OH− transport in poly(arylene indole piperidinium) AEMs remains unclear. This study investigates the effects of four distinct side-chain chemical structures in poly(arylene indole piperidinium) AEMs (specifically, all-carbon side chains (a-PITPC10), side chains with amino groups (a-PITPC7N3), side chains with ethoxy groups (a-PITPC7O3), and side chains with fluoro groups (a-PITPC10F21)) on OH− transport rates and mechanisms using molecular dynamics (MD) simulation methods. The simulation results show that the trend of OH− transport rate at the same hydration number is a-PITPC7N3 < a-PITPC10F21 < a-PITPC10 < a-PITPC7O3. The flexible side chains containing ether oxygen groups have a stronger ability to move, hence the segments have a higher degree of freedom of movement, which is beneficial to the construction of a favorable micro-morphology. At the same time, the cation-dipole interaction between the main chain cation and the ether oxygen group in the side chain of a-PITPC7O3 promotes the aggregation of nearby cationic groups, enlarging the overlapping area of the surrounding hydration shells, thereby facilitating the transport of OH−. Compared to a-PITPC10, in a-PITPC7N3, the strong hydrophilicity of the side chains causes water molecules to tend to disperse, and the bottleneck volume fraction occupied by ion transport channels is the largest, hindering OH− transport. Moreover, in a-PITPC10F21, the strongly hydrophobic side chains cause water molecules to aggregate excessively, forming wide ion transport channels, but their continuity is poor, which is not conducive to OH− transport. The flexible side chains in a-PITPC7O3 facilitate the uniform dispersion of water molecules in the system, forming continuous ion transport channels, which is conducive to improving OH− transport performance. Therefore, the poly(arylene indole piperidinium) AEM with ether oxygen groups (a-PITPC7O3) outperforms other side-chain structured AEMs (a-PITPC10, a-PITPC7N3, and a-PITPC10F21) in improving OH− transport.

Computational design of de novo bioenergetic membrane proteins.

The major energy-producing reactions of biochemistry occur at biological membranes. Computational protein design now provides the opportunity to elucidate the underlying principles of these processes and to construct bioenergetic pathways on our own terms. Here, we review recent achievements in this endeavour of 'synthetic bioenergetics', with a particular focus on new enabling tools that facilitate the computational design of biocompatible de novo integral membrane proteins. We use recent examples to showcase some of the key computational approaches in current use and highlight that the overall philosophy of 'surface-swapping' - the replacement of solvent-facing residues with amino acids bearing lipid-soluble hydrophobic sidechains - is a promising avenue in membrane protein design. We conclude by highlighting outstanding design challenges and the emerging role of AI in sequence design and structure ideation.