Predicting Fixation Tendencies of the H3N2 Influenza Virus by Free Energy Calculation

TL;DR

This study uses free energy calculations to predict how amino acid substitutions in influenza hemagglutinin affect antibody binding, providing insights into viral evolution and immune escape mechanisms.

Contribution

The paper introduces a computational approach using free energy calculations to predict the impact of amino acid substitutions on antibody binding in H3N2 influenza.

Findings

Charged amino acid substitutions tend to decrease antibody binding affinity.

Small amino acid substitutions have minimal impact on binding free energy.

Historical data shows fixed and circulating mutations often increase free energy, aiding immune escape.

Abstract

Influenza virus evolves to escape from immune system antibodies that bind to it. We used free energy calculations with Einstein crystals as reference states to calculate the difference of antibody binding free energy ($\Delta\Delta G$) induced by amino acid substitution at each position in epitope B of the H3N2 influenza hemagglutinin, the key target for antibody. A substitution with positive $\Delta\Delta G$ value decreases the antibody binding constant. On average an uncharged to charged amino acid substitution generates the highest $\Delta\Delta G$ values. Also on average, substitutions between small amino acids generate $\Delta\Delta G$ values near to zero. The 21 sites in epitope B have varying expected free energy differences for a random substitution. Historical amino acid substitutions in epitope B for the A/Aichi/2/1968 strain of influenza A show that most fixed and temporarily circulating substitutions generate positive $\Delta\Delta G$ values. We propose that the observed pattern of H3N2 virus evolution is affected by the free energy landscape, the mapping from the free energy landscape to virus fitness landscape, and random genetic drift of the virus. Monte Carlo simulations of virus evolution are presented to support this view.