Shape Complementarity Research Articles

Discovery of Potent Benzothiazole Inhibitors of Oxidoreductase NQO2, a Target for Inflammation and Cancer

Inhibitors of NQO2 (NRH: quinone oxidoreductase) have potential application in several areas of medicine and pharmacology, including cancer, neurodegeneration (PD and AD), stroke, and diabetes. Here, resveratrol, a known inhibitor of NQO2, was used as the lead by replacing the double bond in resveratrol with a benzothiazole scaffold. Fifty-five benzothiazoles were designed as NQO2 inhibitors and synthesized, comprising five benzothiazole series with 3,5-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 3,4-dimethoxy, and 3,4,5-trimethoxy substituents, the key synthetic step being a Jacobson cyclisation with the appropriate thiobenzamide. All compounds were evaluated in an NQO2 enzyme inhibition assay, with four compounds having IC50 values of <100 nM. The most active (IC50 25 nM) was 6-hydroxy-2-(3’,5’-dihydroxyphenyl)benzo[d]thiazole (15), a good mimetic of resveratrol. Three of the 3’,4’,5’-trimethoxybenzothiazole analogues, with 6-methoxy (40, IC50 51 nM), 6-amino (48, IC50 79 nM), and 6-acetamide (49, IC50 31 nM) substituents, were also potent inhibitors of NQO2. Computational modelling indicated the most active compounds exhibited good shape complementarity and polar interactions with the NQO2 active site. Through the inhibition of NQO2, benzothiazole-based compounds may have the potential to enhance the efficiency of cancer therapies or minimise oxidative damage in neuroinflammation.

Unravelling the Complexity of Amyloid Peptide Core Interfaces.

Amyloids, large intermolecular sandwiched β-sheet structures, underlie several protein misfolding diseases but have also been shown to have functional roles and can be a basis for designing smart and responsive nanomaterials. Short segments of proteins, called aggregation-prone regions (APRs), have been identified that nucleate amyloid formation. Here we present the database of 173 APR crystal structures currently available in the PDB, and a tool, ACW, for analyzing their topologies and the 267 inter-β-sheet interfaces of zipper regions assigned in these structures. We defined a new descriptor of zipper interfaces, the surface detail index (SDi), which quantifies the intertwining between the side chains of both β-sheets of the zipper, an important factor for the molecular recognition and self-assembly of these mesostructures. This allowed a comparative analysis of the zipper interfaces and identification of 6 clusters with different intertwining, steric fit, and size characteristics using three complementary descriptors, SDi, shape complementarity, and buried surface area. 60% of the APR structures are formed by parallel β-sheets, of which 52% belong to the topological class 1. This could be explained by the better fit and a deeper entanglement of the zipper regions of the parallel structures than of the antiparallel structures, as the analysis showed that both their shape complementarity (0.79 vs 0.70) and SDi (1.53 vs 1.32) were higher. The higher abundance of certain residues (Asn and Gln in parallel and Leu and Ala in antiparallel β-sheets) can be explained by their ability to form different ladder-like secondary interaction patterns within β-sheets. Analogous to the hierarchy of protein structure, we interpreted the primary, secondary, tertiary, and quaternary structure levels of APRs revealing different characteristics of the zipper regions for both parallel and antiparallel β-sheet structures, which may provide clues to the structural conditions of amyloid core formation and the rational design of amyloid polymorphs.

Buckybowl-Based Fullerene Receptors.

Buckybowls, bowl-shaped polyaromatic hydrocarbons, have received intensive interest owing to their multifaceted potentials in supramolecular chemistry and materials science. Buckybowls possess unique chemical and physical properties associated with their concave and convex faces. In view of the shape complementarity, which is one of the key factors for host-guest assembly, buckybowls are ideal receptors for fullerenes. In fact, the host-guest assembly between buckybowls and fullerenes is one of the most active topics in buckybowls chemistry, and the resulting supramolecular materials show promising applications in optoelectronics, biomaterials, and so forth. In this tutorial review, we present an overview for the progress on fullerene receptors based on buckybowls over the last decade.

Hierarchical Self-Organization and Disorganization of Helical Supramolecular Columns Mediated by H-Bonding and Shape Complementarity.

H-bonding, shape complementarity, and quasi-equivalence are widely accepted as some of the most influential molecular recognition events mediating biological and synthetic self-organizations. H-bonds are weaker than ionic but stronger than van der Waals forces. However, the directionality of H-bonds makes them the most powerful among all nonbonding interactions. Here, we selected two taper-shaped self-assembling dendrons, one flexible and one rigid, and equipped them with -CO2CH3, -CH2OH, and -COOH at their apex. They demonstrated the hierarchical way in which shape-complementarity in the presence of -CO2CH3 mediated highly ordered helical self-organization for the case of the rigid building block and less ordered helical arrays for the flexible one. Weak H-bonding by -CH2OH unwound the helix from the rigid dendron, yielding a porous column. Due to its quasi-equivalence, the flexible dendron tolerated better the H-bonding by -CH2OH self-organizing a different helical column. The rigid and the flexible dendrons yielded only disorganized nonhelical columns in the presence of -COOH at the apex. This balance between rigidity, flexibility, and tolerance or lack of it to diverse H-bonding architectures indicates that mechanistic elucidation of the self-organization process helps endow it with the same building block, both helical organizations approaching biological precision, and disorganized nonhelical arrangements.

Using a cellulose-complementary oligosaccharide as a tool to probe exposed cellulosic surfaces in cotton fibres and growing plant cell walls.

Cellulosic microfibrils in plant cell walls are largely ensheathed and probably tethered by hydrogen-bonded hemicelluloses. Ensheathing may vary developmentally as hemicelluloses are peeled to enable cell expansion. We characterised a simple method to quantify ensheathed versus naked cellulosic surfaces based on the ability to adsorb a radiolabelled 'cellulose-complementary oligosaccharide', [3H]cellopentaitol. Filter-paper (cellulose) adsorbed 40% and >80% of aqueous 5 nM [3H]cellopentaitol within ∼1 and ∼20 h respectively. When [3H]cellopentaitol was rapidly dried onto filter-paper, ∼50% of it was desorbable by water, whereas after ∼1 day annealing in aqueous medium the adsorption became too strong to be reversible in water. 'Strongly' adsorbed [3H]cellopentaitol was, however, ∼98% desorbed by 6 M NaOH, ∼50% by 0.2 M cellobiose, and ∼30% by 8 M urea, indicating a role for hydrogen-bonding reinforced by complementarity of shape. Gradual adsorption was promoted by kosmotropes (1.4 M Na2SO4 or 30% methanol), and inhibited by chaotropes (8 M urea), supporting a role for hydrogen-bonding. [3H]Cellopentaitol adsorption was strongly competed by non-radioactive cello-oligosaccharides (Cell2-6), the IC50 (half-inhibitory concentration) being highly size-dependent: Cell2, ∼70 mM; Cell3, ∼7 mM; and Cell4-6, ∼0.05 mM. Malto-oligosaccharides (400 mM) had no effect, confirming the role of complementarity. The quantity of adsorbed [3H]cellopentaitol was proportional to mass of cellulose. Of seven cottons tested, wild-type Gossypium arboreum fibres were least capable of adsorbing [3H]cellopentaitol, indicating ensheathment of their microfibrillar surfaces, confirmed by their resistance to cellulase digestion, and potentially attributable to a high glucuronoarabinoxylan content. In conclusion, [3H]cellopentaitol adsorption is a simple, sensitive and quantitative way of titrating 'naked' cellulose surfaces.

Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors.

Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.

Ligand Conformation Controls Assembly of a Helicate/Mesocate, Heteroleptic [Pd2L2L'2] Cages and a Six-Jagged [Pd6L12] Ring.

Molecular building blocks, capable of adopting several strongly deviating conformations, are of particular interest in the development of stimuli-responsive self-assemblies. The pronounced structural flexibility of a short acridone-based bridging ligand, equipped with two monodentate isoquinoline donors, is herein exploited to assemble a surprisingly diverse series of coordination-driven Pd(II) architectures. First, it can form a highly twisted Pd2L4 helicate, transformable into the corresponding mesocate, controlled by temperature, counter anion and choice of solvent. Second, it also allows the formation of heteroleptic cages, either from a mix of ligands with Pd(II) cations or by cage-to-cage transformation from homoleptic assemblies. Here, the acridone-based ligand tolerates counter ligands that carry their donors either in a diverging or converging arrangement, as it can rotate its own coordination sites by 90° and structurally adapt to both situations via shape complementarity. Third, by a near 180° rotation of only one of its arms, the ligand can adopt an S-shape conformation and form an unprecedented C6h-symmetric Pd6L12 saw-toothed six-membered ring.

The Binding Mechanism Between Cyclodextrins and Anticancer Drug Noscapine: A Spectroscopic and Molecular Docking Study.

In this paper the binding of noscapine (NOS) as an anticancer drug with poor bioavailability and low solubility with beta and methyl-beta cyclodextrins (β-CD and M-β-CD) as the biocompatible drug carriers were discussed using ultraviolet-visible, fluorescence and nuclear magnetic resonance spectroscopy, as well as molecular docking. The absorption of NOS changed when it was bound to both cyclodextrins, resulting in a hyperchromic shift. It formed a 1:1 stoichiometry inclusion complex with both cyclodextrins according to the Benesi-Hildebrand equation. The binding affinity was larger in NOS-M-β-CD (5.9 (± 0.66) × 103 M- 1) than NOS-β-CD (3.7 (± 0.22) × 103 M- 1) complex. The fluorescence emission band of NOS at 408nm was quenched when NOS was complexed with β-CD, and enhanced in the presence of M-β-CD, while the shoulder at 350nm was enhanced selectively when NOS was complexed with M-β-CD. The fluorescence quenching of NOS with β-CD showed a negative deviation from the Stern-Volmer. The thermodynamic parameters have been estimated with the help of the Van't Hoff equation in different temperatures, and a dynamic mechanism was proposed for quenching. Also, both ΔH and ΔS have positive values thus the main interactions result in hydrophobic forces. Moreover, the negative value of ΔG indicates that the bonding process is spontaneous. 1H NMR chemical shift changes were observable for NOS and both CDs protons due to the chemical environment changes of some nuclei upon complexation. The molecular docking results revealed that the 1:1 inclusion complex possesses a good molecular shape complementarity score for their most probable structures, and indicated that the M-β-CD inclusion system gave the higher complexation efficiency. The binding energy values for β-CD and M-β-CD were determined to be -6.7 and - 9.5kcal/mol, respectively. These findings suggest the same as the result of experimental tests that the NOS-M-β-CD complex is more stable than the NOS-β-CD complex.

Crossing the Halfway Point: Aptamer-Based, Highly Multiplexed Assay for the Assessment of the Proteome.

Measuring responses in the proteome to various perturbations improves our understanding of biological systems. The value of information gained from such studies is directly proportional to the number of proteins measured. To overcome technical challenges associated with highly multiplexed measurements, we developed an affinity reagent-based method that uses aptamers with protein-like side chains along with an assay that takes advantage of their unique properties. As hybrid affinity reagents, modified aptamers are fully comparable to antibodies in terms of binding characteristics toward proteins, including epitope size, shape complementarity, affinity and specificity. Our assay combines these intrinsic binding properties with serial kinetic proofreading steps to allow highly effective partitioning of stable specific complexes from unstable nonspecific complexes. The use of these orthogonal methods to enhance specificity effectively overcomes the severe limitation to multiplexing inherent to the use of sandwich-based methods. Our assay currently measures half of the unique proteins encoded in the human genome with femtomolar sensitivity, broad dynamic range and exceptionally high reproducibility. Using machine learning to identify patterns of change, we have developed tests based on measurement of multiple proteins predictive of current health states and future disease risk to guide a holistic approach to precision medicine.

Rationalizing Diverse Binding Mechanisms to the Same Protein Fold: Insights for Ligand Recognition and Biosensor Design.

The engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem, which could enable many practical applications of protein biosensors. In this work, we analyzed two engineered biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free-energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

Formation of Linear Plasmonic Heterotrimers Using Nanoparticle Docking to DNA Origami Cages.

The fabrication of complex assemblies with interesting collective properties from plasmonic nanoparticles (NPs) is often challenging. While DNA-directed self-assembly has emerged as one of the most promising approaches to forming such complex assemblies, the resulting structures tend to have large variability in gap sizes and shapes, as the DNA strands used to organize these particles are flexible, and the polydispersity of the NPs leads to variability in these critical structural features. Here, we use a new strategy termed docking to DNA origami cages (D-DOC) to organize spherical NPs into a linear heterotrimer with a precisely defined geometrical arrangement. Instead of binding NPs to the exterior of the DNA templates, D-DOC binds the NPs to either the interior or the opening of a 3D cage, which significantly reduces the variability of critical structural features by incorporating multiple diametrically arranged capture strands to tether NPs. Additionally, such a spatial arrangement of the capture strand can work synergistically with shape complementarity to achieve tighter confinement. To assemble NPs via D-DOC, we developed a multistep assembly process that first encapsulates an NP inside a cage and then binds two other NPs to the openings. Microscopic characterization shows low variability in the bond angles and gap sizes. Both UV-vis absorption and surface-enhanced Raman scattering (SERS) measurements showed strong plasmonic coupling that aligned with predictions by electrodynamic simulations, further confirming the precision of the assembly. These results suggest D-DOC could open new opportunities in biomolecular sensing, SERS and fluorescence spectroscopies, and energy harvesting through the self-assembly of NPs into more complex 3D assemblies.

The molecular determinants of calcium ATPase inhibition by curcuminoids

The natural product curcumin and some of its analogs are known inhibitors of the transmembrane enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). Despite their widespread use, the curcuminoids' binding site in SERCA and their relevant interactions with the enzyme remain elusive. This lack of knowledge has prevented the development of curcuminoids into valuable experimental tools or into agents of therapeutic value. We used the crystal structures of SERCA in its E1 conformation in conjunction with computational tools such as docking and surface screens to determine the most likely curcumin binding site, along with key enzyme/inhibitor interactions. Additionally, we determined the inhibitory potencies and binding affinities for a small set of curcumin analogs. The predicted curcumin binding site is a narrow cleft in the transmembrane section of SERCA, close to the transmembrane/cytosol interface. In addition to pronounced complementarity in shape and hydrophobicity profiles between curcumin and the binding pocket, several hydrogen bonds were observed that were spread over the entire curcumin scaffold, involving residues on several transmembrane helices. Docking-predicted interactions were compatible with experimental observations for inhibitory potencies and binding affinities. Based on these findings, we propose an inhibition mechanism that assumes that the presence of a curcuminoid in the binding site arrests the catalytic cycle of SERCA by preventing it from converting from the E1 to the E2 conformation. This blockage of conformational change is accomplished by a combination of steric hinderance and hydrogen-bond-based cross-linking of transmembrane helices that require flexibility throughout the catalytic cycle.

Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation.

Emerging antibiotic resistance requires continual improvement in the arsenal of antimicrobial drugs, especially the critical macrolide antibiotics. Formation of the macrolactone scaffold of these polyketide natural products is catalyzed by a modular polyketide synthase (PKS) thioesterase (TE). The TE accepts a linear polyketide substrate from the termina PKS acyl carrier protein to generate an acyl-enzyme adduct that is resolved by attack of a substrate hydroxyl group to form the macrolactone. Our limited mechanistic understanding of TE selectivity for a substrate nucleophile and/or water has hampered development of TEs as biocatalysts that accommodate a variety of natural and non-natural substrates. To understand how TEs direct the substrate nucleophile for macrolactone formation, acyl-enzyme intermediates were trapped as stable amides by substituting the natural serine OH with an amino group. Incorporation of the unnatural amino acid, 1,3-diaminopropionic acid (DAP), was tested with five PKS TEs. DAP-modified TEs (TE DAP ) from the pikromycin and erythromycin pathways were purified and tested with six full-length polyketide intermediates from three pathways. The erythromycin TE had permissive substrate selectivity, whereas the pikromycin TE was selective for its native hexaketide and heptaketide substrates. In a crystal structure of a native substrate trapped in pikromycin TE DAP , the linear heptaketide was curled in the active site with the nucleophilic hydroxyl group positioned 4 Å from the amide-enzyme linkage. The curled heptaketide displayed remarkable shape complementarity with the TE acyl cavity. The strikingly different shapes of acyl cavities in TEs of known structure, including those reported here for juvenimicin, tylosin and fluvirucin biosynthesis, provide new insights to facilitate TE engineering and optimization.

Combining Complementarity and Binding Energetics in the Assessment of Protein Interactions: EnCPdock-A Practical Manual.

The combined effect of shape and electrostatic complementarities (Sc, EC) at the interface of the interacting protein partners (PPI) serves as the physical basis for such associations and is a strong determinant of their binding energetics. EnCPdock (https://www.scinetmol.in/EnCPdock/) presents a comprehensive web platform for the direct conjoint comparative analyses of complementarity and binding energetics in PPIs. It elegantly interlinks the dual nature of local (Sc) and nonlocal complementarity (EC) in PPIs using the complementarity plot. It further derives an AI-based ΔGbinding with a prediction accuracy comparable to the state of the art. This book chapter presents a practical manual to conceptualize and implement EnCPdock with its various features and functionalities, collectively having the potential to serve as a valuable protein engineering tool in the design of novel protein interfaces.

Recent advancements in encapsulation of poly aromatic hydrocarbons via macrocyclic host-guest chemistry

Polyaromatic hydrocarbons (PAHs) pose a significant threat to ecosystems and human health due to their widespread presence and persistence in the environment. Conventional remediation techniques often fall short in both efficiency and environmental impact. However, recent advancements in utilizing organic macrocyclic host molecules show considerable promise for effectively sequestering and eliminating PAHs across diverse media. These macrocyclic host molecules play a central role in host–guest chemistry and supramolecular chemistry. It offers distinct advantages by virtue of their precisely tailored cavities and customizable functionalities, greatly enhancing their selective recognition abilities towards guest PAHs. The pursuit of designing and synthesizing novel functional macrocycles has captivated the attention of researchers, driven by the quest to address various challenges in supramolecular research. Over decades of dedicated exploration in host–guest chemistry and supramolecular chemistry, an expansive array of macrocyclic host molecules, constructed from diverse building blocks, have emerged as pivotal tools for encapsulating PAHs. This review presents an overview of the recent progress in the design, synthesis, and application of purely organic macrocyclic molecules in the encapsulation of PAHs. It elucidates the underlying principles that govern their ability to recognise PAHs, such as host–guest interactions, shape complementarity, and π-π stacking interactions. Furthermore, the review discusses various experimental methodologies, such as spectroscopic analyses, chromatography, and computational modelling, employed to assess the efficiency of organic cage molecules in PAH trapping. Additionally, considerations regarding the scalability and environmental implications of organic cage-based PAH trapping systems are addressed. The insights gleaned from this research provide valuable guidance for the development of robust strategies to combat PAH pollution in diverse environmental contexts.

Insilico and Invitro approach to assessing the antimicrobial efficiency of novel AMP variants derived from Lactobacillus sp. against ESKAPE pathogens

Antimicrobial resistance is a major threat worldwide especially when it comes to nosocomial infections caused by ESKAPE bacteria. These pathogens exhibit a remarkable capacity to develop resistance to antimicrobial treatments. Probiotics are receiving considerable attention as potential antimicrobial therapies that are safe, and very effective. The objective of this study is to identify a possible treatment using antimicrobial peptides (AMPs) derived from probiotics. The primary objective is to comprehend the interplay between AMPs and the virulence proteins produced by ESKAPE pathogens that are linked with biofilms. We subjected the 12 peptides found in our earlier investigation to a comprehensive screening approach targeting the virulence proteins of ESKAPE infections by applying shape complementarity concepts and chose the docked complexes with the lowest energy score. The screening process involved assessing binding affinity and interactions with active residues using sophisticated computational tools such as HPEPDOCK, ClusPro 2.0, and AutoDock Vina. The AMP designated as plsa_07 was selected for subsequent examination and validated using molecular dynamic simulations. The in vitro assay demonstrated the antibacterial and antibiofilm properties of AMP plsa_07, with a minimal inhibitory concentration ranging from 1 to 4 μg/ml. The AMP plsa_07 demonstrated biofilm inhibition and eradication action against various bacteria, including E.faecium, S.aureus, K.pneumoniae, A.baumannii, and P.aeruginosa, with a range of effectiveness between 17% and 70%. This study establishes a fundamental foundation for clinical research on the possible application of therapeutic peptides produced from probiotics to address the increasing problem of drug-resistant infections.

Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase.

The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.

EMMAs: Implementation and Assessment of a Suite of Cross-Disciplinary, Case-Based High School Activities to Explore Three-Dimensional Molecular Structure, Noncovalent Interactions, and Molecular Dynamics.

Students frequently develop misconceptions about noncovalent interactions that make it challenging for them to appropriately interpret aspects of molecular structure and interactions critical to myriad applications. We hypothesized that computational molecular modeling and visualization could provide a valuable approach to help address these core misconceptions when students are first exposed to these concepts in secondary school chemistry courses. Here, we present a series of activities exploring biomolecular drug-target interactions using molecular visualization software and an introduction to molecular dynamics methods that were implemented in secondary school classrooms. A pre- and postsurvey approach that incorporated Likert response type, written free response, and drawing-based items demonstrated that students gained an enhanced conceptualization of intermolecular interactions, particularly related to aspects of shape complementarity, after completing the activities. Students also expressed increased comfort with and facility in utilizing different three-dimensional representations of molecules in their postsurvey responses. The activities led to an increased appreciation of interdisciplinary connections of chemistry with mathematics and physics. Overall, the modular activities presented provide a relatively time-efficient and accessible manner to help promote an understanding of a traditionally challenging topic for beginning chemistry students while introducing them to contemporary research tools.

Self-assembly of nanocrystal checkerboard patterns via non-specific interactions

Checkerboard lattices—where the resulting structure is open, porous, and highly symmetric—are difficult to create by self-assembly. Synthetic systems that adopt such structures typically rely on shape complementarity and site-specific chemical interactions that are only available to biomolecular systems (e.g., protein, DNA). Here we show the assembly of checkerboard lattices from colloidal nanocrystals that harness the effects of multiple, coupled physical forces at disparate length scales (interfacial, interparticle, and intermolecular) and that do not rely on chemical binding. Colloidal Ag nanocubes were bi-functionalized with mixtures of hydrophilic and hydrophobic surface ligands and subsequently assembled at an air–water interface. Using feedback between molecular dynamics simulations and interfacial assembly experiments, we achieve a periodic checkerboard mesostructure that represents a tiny fraction of the phase space associated with the polymer-grafted nanocrystals used in these experiments. In a broader context, this work expands our knowledge of non-specific nanocrystal interactions and presents a computation-guided strategy for designing self-assembling materials.

Beyond N-Alkylation: Synthesis, Structure, and Function of N-Amino Peptides.

The growing list of physiologically important protein-protein interactions (PPIs) has amplified the need for compounds to target topologically complex biomolecular surfaces. In contrast to small molecules, peptide and protein mimics can exhibit three-dimensional shape complementarity across a large area and thus have the potential to significantly expand the "druggable" proteome. Strategies to stabilize canonical protein secondary structures without sacrificing side-chain content are particularly useful in the design of peptide-based chemical probes and therapeutics.Substitution of the backbone amide in peptides represents a subtle chemical modification with profound effects on conformation and stability. Studies focused on N-alkylation have already led to broad-ranging applications in peptidomimetic design. Inspired by nonribosomal peptide natural products harboring amide N-oxidations, we envisioned that main-chain hydrazide and hydroxamate bonds would impose distinct conformational preferences and offer unique opportunities for backbone diversification. This Account describes our exploration of peptide N-amination as a strategy for stabilizing canonical protein folds and for the structure-based design of soluble amyloid mimics.We developed a general synthetic protocol to access N-amino peptides (NAPs) on solid support. In an effort to stabilize β-strand conformation, we designed stitched peptidomimetics featuring covalent tethering of the backbone N-amino substituent to the preceding residue side chain. Using a combination of NMR, X-ray crystallography, and molecular dynamics simulations, we discovered that backbone N-amination alone could significantly stabilize β-hairpin conformation in multiple models of folding. Our studies revealed that the amide NH2 substituent in NAPs participates in cooperative noncovalent interactions that promote β-sheet secondary structure. In contrast to Cα-substituted α-hydrazino acids, we found that N-aminoglycine and its N'-alkylated derivatives instead stabilize polyproline II (PPII) conformation. The reactivity of hydrazides also allows for late-stage peptide macrocyclization, affording novel covalent surrogates of side-chain-backbone H-bonds.The pronounced β-sheet propensity of Cα-substituted α-hydrazino acids prompted us to target amyloidogenic proteins using NAP-based β-strand mimics. Backbone N-amination was found to render aggregation-prone lead sequences soluble and resistant to proteolysis. Inhibitors of Aβ and tau identified through N-amino scanning blocked protein aggregation and the formation of mature fibrils in vitro. We further identified NAP-based single-strand and cross-β tau mimics capable of inhibiting the prion-like cellular seeding activity of recombinant and patient-derived tau fibrils.Our studies establish backbone N-amination as a valuable addition to the peptido- and proteomimetic tool kit. α-Hydrazino acids show particular promise as minimalist β-strand mimics that retain side-chain information. Late-stage derivatization of hydrazides also provides facile entry into libraries of backbone-edited peptides. We anticipate that NAPs will thus find applications in the development of optimally constrained folds and modulators of PPIs.