A recent study from Belize and Taiwan shows that four essential proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are well adapted to habitable temperatures and exhibit extreme thermostability, which means temperature changes between the winter and summer months have a negligible effect on the viral spread. The paper is currently available on the bioRxiv* preprint server.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
The evolution of SARS-CoV to SARS-CoV-2, with the subsequent emergence of coronavirus disease 2019 (COVID-19), implies a complex evolutionary and advantageous interplay that created a perfect storm for the rise of the ongoing pandemic.
Thus far, the rate of global infection has undoubtedly demonstrated that SARS–CoV-2 is rather stable when exposed to cold and warm temperatures. Therefore, the initial hopes of strict viral seasonality were not corroborated by epidemiological data.
Nonetheless, the effects of temperature on the receptor-binding domain (RBD) of the spike glycoprotein, main protease (Mpro), macrodomain X (Macro X), and the nucleocapsid protein remain unclear and necessitate urgent clarification with respect to their potential as stable drug targets.
This is what prompted Dr. Paul Morgan from the Faculty of Science and Technology, University of Belize, Belmopan City, Belize, and Dr. Chih-Wen Shu from the National Sun Yat-Sen University, Kaohsiung, Taiwan, to investigate this intriguing issue in depth.
Molecular dynamics simulations
In this study, the research duo employed molecular dynamics simulations to appraise the effect of temperature on those four critical proteins – SARS-CoV-2 RBD, Mpro, Macro X and the nucleocapsid. Temperature that was used ranged from -18 °C to 49 °C.
Furthermore, they have investigated the effect of temperature on the root mean square fluctuation (RMSF) of the critical residues in the RBD, which are ultimately in charge of initializing the interaction with angiotensin-converting enzyme 2 (ACE-2) – the entry point for the infection of lungs cells.
However, it has to be noted that their research approach had several practical limitations. As there is a myriad of proteins in SARS-CoV-2, the assessment is not comprehensive, and it is not easy to simulate changes in humidity by utilizing molecular dynamics simulations (despite its close relationship with temperature).
Four key SARS-CoV-2 proteins are thermostable
"Our findings suggest that the RBD, Mpro, and Macro X, are inherently thermostable, rendering them ideal drug targets with potentially desirable drug binding kinetics," say the authors of this study. "This is because secondary structural changes are often a consequence of inhibitor binding," they add.
Moreover, it has to be noted that the nucleocapsid exhibited the lowest average kinetic energy across the temperature series, whereas Mpro had the highest average kinetic energy. On the other hand, RBD and Macro X displayed comparable kinetic energy and were actually the least responsive when put through the experimental temperature series.
Finally, the elevated rigidity, thermal stability and diminished flexibility observed in the SARS-CoV-2 subregion of RBD is perhaps the driving force behind the substantially enhanced increase in affinity for ACE-2, with far-reaching implications.
A negligible effect on transmissibility
The implications of our study suggests that four essential SARS-CoV-2 proteins are well adapted to habitable temperatures on earth and exhibit extreme thermo-stability", caution study authors in this bioRxiv paper.
As a result, a negligible effect on the transmissibility of SARS-CoV-2 (with respect to temperature changes between winter months and summer months) was noted, which translates to a marginal effect on transmission rates until potent drugs are available.
More importantly, this study actually created a basic framework for unveiling stable promising drug targets for SARS-CoV-2. Still, we understand that the coronavirus machinery is grippingly complex, with potentially many other stabilizing mechanisms and protein-protein interactions that are used to cope with environmental stressors.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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