Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges
Abstract
:1. Introduction
2. Materials and Methods
2.1. Databases
2.1.1. Details and Rationales of Experimental Structural Templates Used for Docking and Dynamics
2.1.2. Dataset of Coronavirus Spikes
2.2. Modeling of Missing Disordered Loops in Spike
2.3. The Spike–Furin Molecular Docking Simulations
2.3.1. Blind ab Initio Docking in Cluspro 2.0
2.3.2. Cross-Validation by Guided Docking in ‘Zdock + IRaPPA Re-Ranking’
2.3.3. Setting Up Appropriate Baselines: The SARS-CoV Spike–Furin Guided Docking in ‘Zdock + IRaPPA Re-Ranking’
2.3.4. Docking Scoring, Ranking and Re-Ranking
2.3.4.1. Buried Surface Area Calculations
2.3.4.2. Shape Complementarity
2.3.4.3. The Sdock Score
2.4. Molecular Dynamic Simulations
2.5. Identifying Salt-Bridges at the Spike–Furin Interface
2.5.1. Analyzing Salt-Bridge Dynamics
2.5.1.1. Salt-Bridge Persistence and Occurrence
2.5.1.2. Average Contact Intensities of Salt-Bridges
2.6. Calculation of Structure-Based Equilibrium Thermodynamic Parameters (∆H, ∆S, ∆G) for the Spike–Furin Binding
2.7. Ramachandran Plot (RP) Derived Parameters to Probe State-Transitions (e.g., Disorder-to-Order)
2.8. Quantifying a Change between Two N-Binned Frequency Distributions and Assessing Its Statistical Significance in Terms of χ2
3. Results and Discussion
3.1. Structural Insight into the Furin Cleavage Mechanisms
3.2. More the Arginines, More the Disorder’ in the FLCSSpike Activation Loops
3.3. Filling Up the Voids in the Spike Structures: The FLCSSpike Disordered Ensembles
3.4. Docking Furin onto Spike: Using the Pentapeptide Activation Loop to Filter and Accumulate Correctly Docked Poses
3.5. Plausible ‘Disorder-to-Order’ Transition Triggered by Salt-Bridge Dynamics at the Spike–Furin Interface: The ‘Salt-Bridge Hypothesis’
3.6. Validations and Cross-Validations of the ‘Salt-Bridge Hypothesis’
3.6.1. In RR1CoV-2
3.6.2. In ZR1CoV-2
3.6.3. In ZR1CoV, the Baseline
3.7. Enthalpy Entropy Compensation Involved in the Spike–Furin Interaction
3.8. Using the Ramachandran Plot to Probe the ‘Disorder-to-Order Transition’ of the SARS-CoV-2 FLCSSpike Loop upon Furin Binding
4. Conclusions and Perspective
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Salt-Bridge | TotC | Framesp | ACI | Pers |
---|---|---|---|---|
294-ASP-S ↔ 349-LYS-F | 1 | 1 | 1.00 | 0.00003 |
683-ARG-S ↔ 191-ASP-F | 4 | 4 | 1.00 | 0.00013 |
654-GLU-S ↔ 357-ARG-F | 23 | 23 | 1.00 | 0.00077 |
683-ARG-S ↔ 264-ASP-F | 196 | 64 | 3.06 | 0.00213 |
682-ARG-S ↔ 233-ASP-F | 73 | 73 | 1.00 | 0.00243 |
654-GLU-S ↔ 359-LYS-F | 149 | 131 | 1.14 | 0.00437 |
683-ARG-S ↔ 230-GLU-F | 247 | 185 | 1.34 | 0.00617 |
685-ARG-S ↔ 236-GLU-F | 251 | 148 | 1.70 | 0.00493 |
214-ARG-S ↔ 112-GLU-F | 729 | 276 | 2.64 | 0.00920 |
627-ASP-S ↔ 359-LYS-F | 1247 | 1173 | 1.06 | 0.03910 |
627-ASP-S ↔ 357-ARG-F | 2763 | 1460 | 1.89 | 0.04867 |
682-ARG-S ↔ 236-GLU-F | 6374 | 1657 | 3.85 | 0.05523 |
685-ARG-S ↔ 264-ASP-F | 16,141 | 7146 | 2.26 | 0.23820 |
654-GLU-S ↔ 193-ARG-F | 45,873 | 19,387 | 2.37 | 0.64623 |
685-ARG-S ↔ 306-ASP-F | 37,148 | 26,969 | 1.38 | 0.89897 |
683-ARG-S ↔ 236-GLU-F | 43,275 | 25,546 | 1.69 | 0.85153 |
682-ARG-S ↔ 230-GLU-F | 75,112 | 27,762 | 2.71 | 0.92540 |
Subjects | <∆Hvdw> | <∆Helec> | <∆Smc> | <∆Ssc> | <∆Gbinding> |
---|---|---|---|---|---|
RR1CoV-2 | −21.722 (2.669) | −8.296 (0.871) | 17.890 (2.276) | 23.386 (3.432) | 3.687 (3.868) |
ZR1CoV-2 | −18.748 (1.871) | −8.617 (0.956) | 16.498 (1.889) | 22.004 (2.243) | 3.043 (3.843) |
ZR1CoV | −13.566 (1.695) | −5.556 (0.582) | 12.663 (1.746) | 14.218 (1.506) | 6.468 (3.135) |
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Roy, S.; Ghosh, P.; Bandyopadhyay, A.; Basu, S. Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges. Vaccines 2022, 10, 301. https://doi.org/10.3390/vaccines10020301
Roy S, Ghosh P, Bandyopadhyay A, Basu S. Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges. Vaccines. 2022; 10(2):301. https://doi.org/10.3390/vaccines10020301
Chicago/Turabian StyleRoy, Sourav, Prithwi Ghosh, Abhirup Bandyopadhyay, and Sankar Basu. 2022. "Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges" Vaccines 10, no. 2: 301. https://doi.org/10.3390/vaccines10020301
APA StyleRoy, S., Ghosh, P., Bandyopadhyay, A., & Basu, S. (2022). Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges. Vaccines, 10(2), 301. https://doi.org/10.3390/vaccines10020301