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 emergence of the Furin-like cleavage site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCSSpike) containing its 681PRRAR685 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 FLCSSpike (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 FLCSSpike 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 seem to be 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 preference for ionic bond formation, even with a lesser number of cationic residues at their potentially polybasic FLCSSpike patches. The interaction energies are suggestive of 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.

Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics.

Intrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to globular proteins, they harbor an enormous amount of physical flexibility enforcing them to be retained in conformational ensembles rather than stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of salt-bridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope of 'self-organized criticality' (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their functional multiplicity. In accordance with the transient nature of 'salt-bridge dynamics', the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in the structural conformations of different IDPs. The insights from the study has the potential to be extended further to benefit structural tinkering of IDPs in their functional characterization and drugging.

Sterile Inflammatory Role of High Mobility Group Box 1 Protein: Biological Functions and Involvement in Disease.

High mobility group box 1 protein (HMGB1), a sterile inflammatory molecule and damage-associated molecular pattern (DAMP) released from various cells during stress has been implicated in inflammation. Several reports show that there is a direct relationship between inflammation and cardiovascular diseases (CVDs) such as thrombosis, hypertension, insulin resistance, preeclampsia, etc. Here, we intend to summarize the concept of the emerging link between HMGB1 and CVDs. Furthermore, we will discuss the possible therapeutic strategies that target HMGB1 for the treatment of different CVDs.