Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges

Abstract

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.

Prediction of protein-protein interaction sites in intrinsically disordered proteins

“…When disordered proteins participate in protein-protein interactions, ionic bonds are formed between oppositely charged amino acid side-chains, i.e., salt bridges. Studies (Basu and Biswas, 2018;Roy et al, 2022) have found that the formation of salt bridges contributes to the generation of local rigid structure of IDP, and triggers the disordered to ordered transition of IDP. For example, α -synuclein binds with tubulin to form an inter-chain salt bridge and mediate the transformation of protein conformation (Basu and Biswas, 2018).…”

“…For example, α -synuclein binds with tubulin to form an inter-chain salt bridge and mediate the transformation of protein conformation (Basu and Biswas, 2018). The arginines of FLCS Spike and the anions of Furin form dynamically Frontiers in Molecular Biosciences frontiersin.org interchangeable and durable salt bridge networks at the Spike-Furin binding interface, which triggers the transition from disorder to order (Roy et al, 2022). Therefore, we believe that the performance of the protein-binding sites predictor can be further improved by adding the feature of salt bridges in disordered proteins.…”

“…It has been found that the binding of IDP with corresponding proteins will lead to the transition from disorder to order. For instance, the disordered regions of E-cadherin turn to order format after interacting with β-catenin (Dyson and Wright, 2002); the disordered protein DFF45 interacts with DFF40 to transform into an ordered state (Zhou et al, 2001); the Furin-like cleavage site exists at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS Spike ), and the "disorder-to-order transition" of Spike-Furin complex has been found (Roy et al, 2022). In addition, some ordered proteins interacting with other molecules leads to the unfolding of self-inhibiting domains and activates biological functions (Uversky, 2013).…”

Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations

“…Additionally, protein-peptide interactions were also monitored throughout the simulation time using the Maestro package. For computing the energy terms, following a similar methodology as Roy et al (Roy et al, 2022), the total energy values (kcal/mol) were collected at 10 ps intervals across the 300 ns MD simulation trajectory (a total of 30,000 timestamps) for WT Aβ 1-42 -cyclotide complex and its control trajectory (WT Aβ 1-42 unbound), and mutant Aβ 1-42 (Y10A)-cyclotide complex and its control trajectory (Aβ 1-42 Y10A unbound) using the Simulation Quality Analysis (SQA) module in the Desmond package. The difference in total energy (ΔE) between the cyclotide bound and unbound forms along the time series (i; 10 ps intervals) was calculated using the formulae:…”

Editorial: From the hydrophobic core to the globular-disorder interface: New challenges and insights into protein design

“…Furthermore, since the discovery of intrinsically disordered proteins (IDPs), with their characteristic binding promiscuity attributed to their physical flexibility, attempts to understand and design protein disorder transitions ( Bandyopadhyay and Basu, 2020 ; Roy et al, 2022 ) and to address the “globular/ordered–disordered” evolutionary interface ( Nagibina et al, 2020 ) in proteins are among the most intriguing challenges in this field. It is but natural that designs of ordered proteins and IDPs should use different principles and the field is enriching with ideas and findings on both ( Figure 1 ).…”