Molecular Dynamics Simulation of the Influenza A(H3N2) Hemagglutinin Trimer Reveals the Structural Basis for Adaptive Evolution of the Recent Epidemic Clade 3C.2a

Abstract

Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C.2a and is characterized by attenuated ability to agglutinate nonhuman erythrocytes. Comparison of the equilibrated structures of the glycosylated HA trimers with and without the 3C.2a-specific mutations reveals that the mutations could induce a drastic reduction in the apical space for the ligand binding via glycan-shield rearrangement. The results suggest that the 3C.2a strain has evolved an HA structure that is advantageous for evading pre-existing antibodies, while also increasing the ligand binding specificity. These findings have structural implications for our understanding of the phenotypic changes, evolution, and fate of influenza A(H3N2).

Allosteric Regulation of HIV-1 Capsid Structure for Gag Assembly, Virion Production, and Viral Infectivity by a Disordered Interdomain Linker

“…MD simulation of HIV-1 capsid monomer. HIV-1 capsid models were subjected to MD simulations essentially as described previously for viral structural proteins and enzymes (36,(74)(75)(76). Briefly, the simulations were done by the pmemd module in the Amber 16 program package (54) with the ff14SB force field (77) and the TIP3P water model for simulations of aqueous solutions (78).…”

“…Calculation of RMSF. RMSFs were calculated as described previously (74)(75)(76) to quantify structural dynamics of molecules in the MD simulations. RMSFs of the C␣ atoms were calculated to obtain information on atomic fluctuations of individual amino acid residues during MD simulations.…”

Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility

“…An antigenically drifted descendant of the original 1968 H3N2 strain, designated as clade 3c2.A H3N2 viruses, emerged during the 2014-2015 influenza season 6 and continues to circulate at high levels across most parts of the world 7 . 3c2.A H3N2 viruses are unique because they possess a key glycosylation site that shields HA antigenic site B, which is a major target of neutralizing antibodies 8 .…”

Antigenic assessment of the H3N2 component of the 2019-2020 Northern Hemisphere influenza vaccine

“…3N2 influenza viruses include many subclades with different genetic and antigenic properties 1 . Antigenically distinct 3c2.A and 3c3.A H3N2 viruses emerged during the 2014-2015 season 2 , which led to a major vaccine mismatch and low vaccine effectiveness 3,4 . 3c2.A H3N2 viruses have predominated since then and antigens from these viruses have been included in vaccine formulations for the 2015-2016 to 2018-2019 seasons 1,5 .…”