SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape.

Area of Science:

• Virology
• Molecular Biology
• Biophysics

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD) mutations drive variant evolution.
• Variants of concern, like Delta, emerge due to immune pressure from vaccination, increasing transmissibility and immune escape.
• Understanding mutation impacts on binding affinity and immunity is critical for pandemic control.

Purpose of the Study:

• To analyze the physical mechanisms behind RBD mutations affecting SARS-CoV-2 binding affinity to ACE2 and antibodies.
• To investigate the role of entropy-enthalpy compensation in protein-protein interactions within SARS-CoV-2.
• To propose a novel calculation method for protein-protein complex binding energies.

Main Methods:

• Analysis of entropy-enthalpy compensation and Gibbs free energy changes.
• Evaluation of RBD mutations' impact on binding affinity with ACE2 and antibodies.
• Application of a new binding energy calculation method based on entropy-enthalpy compensation.

Main Results:

• Existing mutations may have maximized transmissibility; a specific mutation at RBD position 498 could enhance binding affinity.
• All studied RBD-antibody and RBD-ACE2 complexes adhere to the entropy-enthalpy compensation rule.
• The L452R mutation reduces antibody binding affinity, contributing to breakthrough infections in vaccinated individuals.

Conclusions:

• Mutations altering residue hydrophobicity/hydrophilicity in the spike RBD can lead to breakthrough infections by disrupting binding site complementarity.
• Entropy-enthalpy compensation is a fundamental driving force for SARS-CoV-2 protein-protein interactions.
• The study provides insights into viral evolution and aids in designing effective countermeasures against SARS-CoV-2 variants.