Stability of the Influenza Virus Hemagglutinin Protein Correlates with Evolutionary Dynamics

Abstract

One of the constraints on fast-evolving viruses, such as influenza virus, is protein stability, or how strongly the folded protein holds together. Despite the importance of this protein property, there has been limited investigation of the impact of the stability of the influenza virus hemagglutinin protein—the primary antibody target of the immune system—on its evolution. Using a combination of computational estimates of stability and experiments, our analysis found that viruses with more-stable hemagglutinin proteins were associated with long-term persistence in the population. There are two potential reasons for the observed persistence. One is that more-stable proteins tolerate destabilizing mutations that less-stable proteins could not, thus increasing opportunities for immune escape. The second is that greater stability increases the fitness of the virus through increased production of infectious particles. Further research on the relative importance of these mechanisms could help inform the annual influenza vaccine composition decision process.

Superfunneled Energy Landscape of Protein Evolution Unifies the Principles of Protein Evolution, Folding, and Design

“…Therefore, larger thermodynamic stability and kinetic accessibility often lead to larger gaps which can give rise to larger designability. This is consistent with some previous studies [27,52,53]. Larger energy gap of a sequence implies a greater ability to tolerate mutations, i.e.…”

“…Thus, we suggest that protein folding is not an accidental event but the result of the actions or constrains from natural selection. In this view, the emergence of the special ensemble of naturally occurring protein sequences and structures is driven by the folding requirements of both thermodynamic stability and kinetic accessibility [25][26][27].…”

Characterizing Emerging Canine H3 Influenza Viruses

“…Plaque assays were performed on MDCK cells plated at 1x10 6 cells/well in 6-well tissue culture plates and grown to confluency as described [68]. TCID 50 assays were performed on confluent MDCK cells in 96-well tissue culture plates as described [68]. Endpoint calculations were determined by the Reed-Muench algorithm [67].…”

Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin

“…Influenza hemagglutinin (HA) is a uniquely attractive model protein for systematically and quantitatively evaluating whether and how ER proteostasis mechanisms impact client protein mutational tolerance. The folding of HA is perhaps as well-delineated as for any other membrane protein, and HA interacts extensively with components of the host cell’s ER proteostasis network ( Chen et al, 1995 ; Daniels et al, 2003 ; Sauter et al, 1992 ; Nakajima et al, 1986 ; Frabutt et al, 2018 ; Hurtley et al, 1989 ; Hebert et al, 1997 ; Ueda and Sugiura, 1984 ; Skehel and Wiley, 2000 ; Klein et al, 2018 ; Gamblin et al, 2004 ; Pankow et al, 2015 ). Co-translationally, HA is heavily N -glycosylated and engages the ER’s lectin chaperones, calnexin and calreticulin, which increase HA’s folding efficiency and prevent misfolding ( Chen et al, 1995 ; Daniels et al, 2003 ; Hebert et al, 1997 ).…”