[SCAN] Fusing simulation and experiment: Structure and activity studies on the influenza fusion peptide

SCAN

Title: Fusing simulation and experiment: Structure and activity studies on the influenza fusion peptide

Speaker: Diana Lousa

Affiliation: Cláudio M. Soares Lab – Protein Modeling

Abstract:

The emergence of an influenza pandemic is one of the biggest health threats of our time and, therefore, there is an urgent need to develop vaccines and drugs against a broad spectrum of influenza viruses (IV). A promising strategy to combat IV is to inactivate the fusion process between the viral and host membranes, which is mediated by the surface protein hemagglutinin (HA). During this process, the N-terminal region of HA, known as fusion peptide (FP), inserts into the host membrane. Although it has been shown that the FP plays a crucial role in the fusion process, the molecular effect of the peptide remains unclear

In order the shed light into this problem, we used a combination of state-of-the-art experimental and simulation techniques to analyse the WT influenza FP and four mutants. Fluorescence based methods were used to analyse the partition coefficient of the WT and mutant peptides in model membranes, and their ability to promote lipid-mixing was analysed using a (FRET)-based assay. To rationalize the results obtained in these experiments, we analysed the energy landscape of the peptides by performing bias-exchange metadynamics (BE-META) simulations. This allowed us to characterize the conformational properties of the WT peptide in a model membrane and understand how this structure is affected by the mutations studied. This study also elucidated the factors that explain the reduced activity of the mutants, which contributes to a better understanding of the role of the influenza FP in the fusion process.