The membrane remodeling machinery of influenza A virus
Name of applicant
Jesper Jonasson Madsen
Amount
DKK 233,333
Year
2017
Type of grant
Internationalisation Fellowships
What?
My project pertains to membrane remodeling by the matrix 2 (M2) protein, which is a key step in the replication cycle of influenza A virus. Specifically, I will study the curvature-sorting and inducing properties of the protein, and how various lipid moieties play a role in the membrane remodeling and ultimately scission, whereby the membrane envelope it "cut" to release the newly formed virus.
Why?
Influenza A is a virus that we have all been subjected to, primarily through the annual outbursts during what is commonly known as "Flu season." In its mild subtypes, the flu typically gives rise to symptoms such as fever, coughing, sneezing, sore throat, runny nose, headache, chills, fatigue, and nausea. However, the WHO estimate that the flu annually causes in approximately 250,000 to 500,000 deaths world-wide. Furthermore, the (likely) deadliest pandemic in human history (year 1918) was caused by an influenza virus.
How?
I will explore the effects of the flu M2 protein on membrane remodeling using state-of-the-art multiscale simulation techniques to help elucidate the molecular mechanism by which M2-driven membrane remodeling happens at multiple physical scales: On the atomistic scale, specific amino acid residue interactions involved in the scission process will be investigated and we will in turn propose experimental mutagenesis sites to allow the manipulation of local curvature-altering behaviour. On the mesoscopic scale, we will use systematic coarse-grained (CG) dynamics simulations to study the aggregation of the flu proteins in the lipid assemblies (vesicles) and the "big-picture" patterns responsible for reshaping of the membrane.