This study systematically explores the chemical space governing tripeptide self-assembly by leveraging a high-throughput Suzuki-Miyaura cross-coupling platform. A library of 42 commercially available arylboronates—spanning diverse hydrophobicity, polarity, charge states, and aromaticity—was used to derivatize a common tripeptide precursor (P0), enabling direct comparison of structural effects on supramolecular behavior. The results reveal clear trends in how molecular modifications dictate aggregation propensity, nanostructure morphology, and functional output.
Hydrophobic aryl groups consistently promoted fibrillation, with enhanced effects observed when methylene or methyl linkers were introduced (e.g., compounds 2–10) or when electron-withdrawing groups such as cyano (11) or fluorine (12–15) were present. These modifications increased lipophilicity and strengthened π–π interactions, thereby lowering the critical aggregation concentration (c*). In contrast, incorporation of anionic groups like –COOH (22, 23, 27) suppressed assembly due to electrostatic repulsion. This inhibition could be reversed by esterification (21), which neutralized the negative charge at physiological pH, highlighting the importance of charge masking over mere removal of ionization. However, amidation (32, 33) failed to restore fibrillation, likely due to the higher polarity and lower hydrophobicity of amides compared to esters, as reflected in logP values.
The sulfonate group (–SO₃H, 27) exhibited strong deactivating effects that could not be overcome by simple charge neutralization (28–30), underscoring the influence of intrinsic polarity. Sulfonyl groups are significantly more polar than carbonyls, as evidenced by the higher dielectric constant of dimethyl sulfoxide (DMSO, EN = 0.444) versus acetone (EN = 0.355). This polarity impedes hydrophobic collapse, even when charge is removed. Similarly, polar substituents such as hydroxyl (–OH, 26) and hydroxymethyl (–CH₂OH, 24, 25) inhibited association, while their ether analogs (–OCH₃, 16, 17, 20) restored fibrillation capacity—further confirming the role of hydrophobicity over hydrogen-bonding potential.
Notably, subtle differences in molecular architecture led to dramatic functional divergence. For instance, both –CH₂OH (24, 25) and –OCH₃ (17) share identical atomic composition but differ in polarity: alcohols are more polar than ethers. Consequently, hydroxymethyl derivatives acted as structural deactivators, whereas methoxy derivatives served as potent fibrillation promoters. This distinction emphasizes that small changes in functional group chemistry can profoundly alter supramolecular outcomes.
Aromaticity also played a decisive role. While furan-based heterocycles (34, 35) failed to induce aggregation, their sulfur-containing counterparts—thiophenes (36, 37)—triggered robust fibrillation. This difference stems from thiophene’s greater aromatic stabilization energy compared to furan, facilitating stronger π–stacking interactions.TudorSN Antibody Cancer Further evidence came from comparing naphthol (38) and phenol (26): the larger, more conjugated naphthol group yielded significantly enhanced fibrillation, demonstrating that extended conjugation enhances intermolecular interactions.Ron Antibody supplier
Large fused aromatic systems—including benzo[b]thiophene (39, 40), benzo[b]furan (41), and indole (42)—consistently induced hierarchical self-assembly, reinforcing the central role of aromaticity in driving supramolecular order. As steric bulk increased, so did the width of resulting nanofibrils, with bulky arylboronates (4–8) favoring planar ribbon formation over twisted or helical structures. This suggests that steric hindrance promotes lateral stacking and reduces torsional strain, stabilizing two-dimensional architectures.
TEM imaging revealed a rich diversity of morphologies: thin fibrils (a), helical ribbons (b), twisted ribbons (c), wide planar ribbons (d), laminated ribbons (e), and thin ribbons (f).PMID:34729690 These variations were directly linked to the electronic and steric profile of the appended aryl group. The ability to tune nanostructure shape through chemical design opens new avenues for tailoring material properties such as mechanical strength, surface area, and interaction dynamics.
In summary, this work establishes a comprehensive structure-function map for peptide self-assembly. By classifying arylboronates into four categories—hydrophobic/aromatic promoters, polar/deactivators, charged inhibitors, and large conjugated enhancers—the study provides predictive guidelines for rational design. The strong correlation between logP values and fibrillation behavior confirms that hydrophobicity is a dominant factor, though aromaticity and steric effects cannot be overlooked. Together, these findings demonstrate that combinatorial diversification via Suzuki-Miyaura coupling enables precise control over supramolecular architecture, offering a powerful strategy for engineering functional peptide materials with tailored physical and biological properties.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com