Capturing a crucial 'disorder-to-order transition' at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

The COVID-19 origin debate has greatly been influenced by Genome comparison studies of late, revealing the seemingly sudden emergence of the Furin-Like Cleavage Site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS_Spike) containing its 681_PRRAR_685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a disorder-to-order transition of the FLCS_Spike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike-Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCS_Spike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seems the other key characteristic features of the Spike-Furin binding in SARS-CoV-2 allowing the system to breathe - a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike-Furin binding events generally in the coronavirus lineage seems to have a preference for ionic bond formation, even with lesser number of cationic residues at their potentially polybasic FLCS_Spike patches. The interaction energies are suggestive of a characteristic metastabilities attributed to Spike-Furin interactions generally to the coronavirus lineage - which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. The current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution but also add substantially to the existing theories of proteolytic cleavages.

Conservation and Identity Selection of Cationic Residues Flanking the Hydrophobic Regions in Intermediate Filament Superfamily

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) are relatively conserved in evolution. In contrast, the cationic residues that are not adjacent to the hydrophobic domain (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.

Design and Synthesis of Novel Peptides to Protect Ferulic Acid against Ultraviolet Radiation Based on Domain Site IIA of Bovine Serum Albumin

Ferulic acid (FA) is known for its excellent antioxidant properties, which can provide many health benefits. One of its drawbacks is its instability under UVA light, which limits its potency. In this study, the new peptides LW2 (QNKRFYFRKNQ) and CW2 (a cyclic form of LW2) were designed based on bovine serum albumin site IIA conformation. A UVA irradiation experiment was performed to investigate the protective ability of these peptides towards FA against UVA damage. The percentages of FA remaining under UV irradiation due to the protection of CW2 and LW2 were 83% and 76%, respectively. The results showed the importance of the cationic residues and hydrophobic residues included in the peptide sequences. Moreover, the cyclic rigid structure showed greater protective ability as compared to its linear counterpart.

Design and Synthesis of Novel Peptides to Protect Ferulic Acid Against Ultraviolet Radiation Based on Domain Site IIA of Bovine Serum Albumin

Ferulic acid (FA) is known for its excellent antioxidant properties that can provide a lot of health benefits. One of its drawbacks is being unstable under UVA light that limits its potency. In this study, new peptides LW2 (QNKRFYFRKNQ) and CW2 (a cyclic form of LW2) have been designed based on bovine serum albumin site ⅡA conformation. UVA irradiation experiment was performed to investigate the protective ability of these peptides towards FA against UVA damage. The percentage of FA remaining under UV irradiation by the protection of CW2 and LW2 was 83%, 76% respectively. The results showed the importance of the cationic residues and hydrophobic residues included in the peptide sequences. Moreover, the cyclic rigid structure showed more protecting ability over that of the linear counterpart.

Evaluating the effects of hydrophobic and cationic residues on antimicrobial peptide self-assembly

Four PAF26 peptide derivatives were used to study the effects of hydrophobic and cationic residues on self-assembly behaviours. It was found that peptide with different number of hydrophobic and cationic residues had different secondary conformation and microstructure.