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The interplay between the hydrophobic interactions generated by the nonpolar region and the proximal functional groups within nanometers of the nonpolar region offers a promising strategy to manipulate the intermolecular hydrophobic attractions in an artificial molecule system, but the outcomes of such modulations in the building of a native protein architecture remain unclear. Here we focus on the intermediate filament (IF) coiled-coil superfamily to assess the conservation of positively charged residue identity via a biostatistical approach. By screening the disease-correlated mutations throughout the IF superfamily, 10 distinct hotspots where a cation-to-cation substitution is associated with a pathogenic syndrome have been identified. The analysis of the local chemical context surrounding the hotspots revealed that the cationic diversity depends on their separation distance to the hydrophobic domain. The nearby cationic residues flanking the hydrophobic domain of a helix (separation 1 nm) tolerate higher levels of variation and replaceability. We attribute this bias in the conservation degree of the cationic residue identity to reflect the interplay between the proximal cations and the hydrophobic interactions.

Ions are crucial in modulating the protein structure. For the free ions in bulk solution, ammonium is kosmotropic (structure forming) and guanidinium is chaotropic (structure breaking) to the protein structure within the Hofmeister series. However, the effect of immobilized ions on a protein surface is less explored. Herein, we explored the influence of two immobilized cations (ammonium in the side chain of lysine and guanidinium in the side chain of arginine) on the folding and assembly of melittin. Melittin adopts an α-helix structure and is driven by hydrophobic interactions to associate into a helical bundle. To test the influence of immobilized cations on the peptide structure, we designed the homozygous mutants exclusively containing ammonium (melittin-K) or guanidinium (melittin-R) and compared the differences of melittin-K vs. melittin-R in their folding, assembly, and molecular functions. The side chains of lysine and arginine differ in their influences on the folding and assembly of melittin. Specifically, the side chain of R increases the α-helical propensity of melittin relative to that of K, following an inverse Hofmeister series. In contrast, the side chain of K favors the assembly of melittin relative to the side chain of R in line with a direct Hofmeister series. The opposite regulatory effects of immobilized cations on the folding and assembly of melittin highlight the complexity of the noncovalent interactions that govern protein intermolecular architecture.

Substantial controversies exist in the exploration of the molecular mechanism of heart failure (HF) and pose challenges to the diagnosis of HF and the discovery of specific drugs for the treatment. Recently, cardiac transthyretin (TTR) amyloidosis is becoming recognized as one of major causes of underdiagnosed HF. The investigation and modulation of TTR misfolding and amyloidal aggregation open up a new revenue to reveal the molecular mechanisms of HF and provide new possibilities for the treatment of HF. The aim of this review is to briefly introduce the recent advances in the study of TTR native and misfolding structures, discuss the correlation between the genotype and phenotype of cardiac TTR amyloidosis, and summarize the therapeutic applications of TTR structural stabilizers in the treatment of TTR amyloidosis-associated HF.

Diverse natural/artificial proteins have been used as building blocks to construct a variety of well-ordered nanoscale structures over the past couple of decades. Sophisticated protein self-assemblies have attracted great scientific interests due to their potential applications in disease diagnosis, illness treatment, biomechanics, bio-optics and bio-electronics, etc. This review outlines recent efforts directed to the creation of structurally defined protein assemblies including one-dimensional (1D) strings/rings/tubules, two-dimensional (2D) planar sheets and three-dimensional (3D) polyhedral scaffolds. We elucidate various innovative strategies for manipulating proteins to self-assemble into desired architectures. The emergent applications of protein assemblies as versatile platforms in medicine and material science with improved performances have also been discussed.

The nanovesicles extracted from the plant and herbal decoctions are identified as a new class of nanomedicine. They are involved in interspecies chemical communication across the plant and animal kingdoms and display a therapeutic potential against a variety of diseases. Herein, we review the recent progress made in the medical applications of plant-derived nanovesicles in the aspects of anti-inflammation, anti-cancer, tissue regeneration, and modulating commensal microbiota. We further summarize the cellular and molecular mechanisms underlying the physiological functions of plant-derived nanovesicles. Overall, plant-derived nanovesicles provide an alternative to conventional synthetic drugs and present exciting opportunities for future research on disease therapy.

Physical and biochemical differences between tumor tissues and normal tissues provide promising triggering factors that can be utilized to engineer stimuli-responsive drug delivery platforms for cancer treatment. Rationally designed peptide-based supramolecular architectures can perform structural conversion by responding to the tumor microenvironment and achieve the controlled release of antitumor drugs. This mini review summarizes recent approaches for designing internal trigger-responsive drug delivery platforms using peptide-based materials. Peptide assemblies that exhibit a stimuli-responsive structural conversion upon acidic pH, high temperature, high oxidative potential, and the overexpressed proteins in tumor tissues are emphatically introduced. We also discuss the challenges of current peptide-based supramolecular delivery platforms against cancer.