Increased Gibbs energy of binding indicates greater infectivity of SARS-CoV-2 BA.2.75

By Dr. Chinta SidharthanOct 27 2022Reviewed by Benedette Cuffari, M.Sc.

A recent BioTech journal study explores the thermodynamic properties, such as antigen-receptor binding rate and Gibbs energy of binding, of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2.75 to understand its increased transmissibility.

Study: Omicron BA.2.75 Subvariant of SARS-CoV-2 Is Expected to Have the Greatest Infectivity Compared with the Competing BA.2 and BA.5, Due to Most Negative Gibbs Energy of Binding. Image Credit: Firn / Shutterstock.com

Background

Microorganisms are open thermodynamic systems that perform biological, chemical, and physical interactions with the environment. Previous studies on the thermodynamics of these interactions have explored the driving force for microorganism growth and calorimetric parallels between the laws of thermodynamics and biological evolution. In addition, the thermodynamic properties of viruses like monkeypox and Vaccinia viruses have also been studied.

The ribonucleic acid (RNA) of SARS-CoV-2 has mutated to produce variants with different infectivity and immune evasion properties. SARS-CoV-2 infects the host cell by binding its spike protein trimer to the angiotensin-converting enzyme 2 (ACE-2) receptor.

The increased infectivity of some SARS-CoV-2 variants could be explained by enhanced binding between the spike protein and the ACE-2 receptor. Thus, the receptor binding rate and Gibbs free energy of binding can be compared across variants to assess infectivity.

About the study

The present study used existing literature to obtain dissociation equilibrium constants, as well as association and dissociation rate constants, for the ACE-2 receptor to the spike protein of different SARS-CoV-2 variants.

The Gibbs energy of binding was calculated using the dissociation equilibrium constant, which was then used to calculate the rate of binding of the spike protein to the ACE-2 receptor for each of the SARS-CoV-2 variants. Kinetic, exponential, and thermodynamic approaches were employed to determine the entry rate for SARS-CoV-2 variants.

The kinetic approach is based on the law of mass action and uses the association and dissociation rate constants, whereas the exponential approach uses an exponential equation based on nonequilibrium thermodynamics. The thermodynamic approach applies the binding phenomenological equation.

Study findings

The Gibbs energy of binding of the SARS-CoV-2 Omicron subvariant BA.2.75 was -49.41 kJ/mol, while that of BA.4 and BA.5 were -45.81 kJ/mol and -44.95 kJ/mol, respectively.

The BA.2.75 variant carrying the N460K mutation also had the highest entry rate of 1.49 × 10^-15 M/s as compared to BA.2 and BA.5, which had rates of 6.58 × 10^-17 M/s and 1.19 × 10^-17 M/s, respectively. The binding rate of the SARS-CoV-2 Omicron variants increased from BA.2 to BA.5.

The spread of SARS-CoV-2 depends on its infectivity and pathogenicity. Infectivity is determined by the rate of viral entry in susceptible cells, whereas pathogenicity reflects viral multiplication rates within the host cell.

SARS-CoV-2 entry is dependent upon interactions between its spike protein and the host ACE-2 receptor, which is determined by the Gibbs energy of binding. Mutations in the spike protein change the interaction between antigen and receptor, thereby altering certain thermodynamic properties, such as dissociation equilibrium and rate constants.

The higher entry rate and Gibbs energy of binding for the Omicron BA.2.75 subvariant likely explain the greater infectivity of BA.2.75 as compared to other dominant subvariants BA.4 and BA.5. Moreover, these characteristics may also indicate that BA.2.75 could be the next globally dominant SARS-CoV-2 Omicron subvariant.

The S446G and N460K mutations in BA.2.75 enhance its neutralization evasion properties. Immune evasion likely gives subvariants an advantage in establishing global dominance by increasing transmissibility.

However, the study findings indicate that immune evasion alone is not responsible for increased infectivity. In fact, higher Gibbs energy of binding and entry rates also appear to improve the subvariant’s infectivity by increasing the rate of spike protein and ACE-2 receptor binding.

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, multiple SARS-CoV-2 variants and subvariants have emerged with mutations that enhance antigen binding and immune escape. Furthermore, new viral variants have competed with existing dominant variants, with some that have managed to replace the older variant and achieve global dominance.

Mutations in emergent SARS-CoV-2 variants alter the thermodynamic properties of antigen binding, as they result in chemical changes in the protein structure. Thermodynamic parameters, such as Gibbs energy of binding and the entry rate, could be indicators of increased infectivity. Thus, this information could help predict the potential dominance of a new variant.

Conclusions

The study findings suggest that the higher Gibbs energy of binding and greater entry rate of the SARS-CoV-2 Omicron subvariant BA.2.75 are responsible for its increased infectivity and predict its potential global dominance in the near future.