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Membrane fusion mechanism of Influenza Hemagglutinin: a simulation and biophysical approach

Instituto de Tecnologia Química e Biológica
Project classification

Scientific area

1.4 Chemical sciences


Organic chemistry

Project description

Project title

Membrane fusion mechanism of Influenza Hemagglutinin: a simulation and biophysical approach

Scientific Coordinator's name:

Cláudio Soares

Scientific Coordinator's e-mail:

Principal R&D Unit:

Instituto de Tecnologia Química e Biológica

Other R&D Units involved in the project:

Instituto de Medicina Molecular

Project keyword(s)

Hemagglutinin, virus, fusion peptide, Molecular modelling

Short abstract and comments

Influenza viruses (IV) are responsible for worldwide outbreaks of flu, which can have dramatic consequences, as demonstrated by the recent pandemic caused by the new strain of IV, H1N1. Unfortunately, due to high genetic variability and insufficient knowledge about the infection process, we have very few weapons against these viruses. Hemagglutinin (HA), which can constitute an important drug target, is a glycoprotein found on the membrane of IV. This protein is involved in the initial steps of the infection process of the virus, by promoting its fusion with the cell. Despite its importance in IV, structural knowledge about its action and its molecular mechanisms is still limited. HA comprises two chains, HA1 and HA2. HA1 contains surface regions used in the initial step of the infection, to bind to cell surface receptors containing sialic acid. After internalization of the virus into endosomes, the low pH induces dramatic structural changes in HA1, allowing the fusion peptide, located in the N¬terminal of HA2, to become exposed and to promote the fusion of viral and cell membranes. In the C¬terminal of the HA2 chain there is another important segment, the transmembrane peptide, which anchors HA to viral membranes, but the molecular details of the interaction between this peptide and the membrane are scarce. Another important segment region of HA is the hinge peptide, which, during the conformational change experienced by HA in endosomes, changes its conformation from coil to helix, projecting the fusion peptide against the membrane. Our objective in this project is to understand the molecular details of HA mediated membrane interactions using a unique combination of simulation and experiments, applied to the HA molecule itself, and to the fusion, transmembrane and hinge peptides separately. Most experimental techniques in the field of protein¬membrane interactions provide macroscopic or indirect microscopic pictures, lacking molecular and atomic detail. The opposite occurs for MD simulation, whose reign is the microscopic world. However, simulations suffer from uncertainties arising from simplified physical descriptions and from the short times that can be treated. Combining these two types of approaches in the same problem seems to be the natural choice, although one rarely done. Here, we have assembled a team, both versed in simulation and experiments, to study protein/peptide¬membrane interactions, trying to unravel the mechanism of HA mediated membrane fusion. The fusion peptide is the simplest system to understand the membrane fusion process. Several simulations of this peptide have been reported, but we want to apply approaches with higher physical realism, while ensuring that proper statistics are achieved. We will investigate the conformational changes observed upon its interaction with membranes. Preliminary studies show very encouraging results. We will also test the interaction of the transmembrane peptide with membranes and the conformational transition from coil to helix of the hinge peptide at low pH. These theoretical studies will have an experimental counterpart, where the conformation of the peptides, their partition between aqueous and membrane phases, their location in the membrane, and their surface aggregation and vesicle fusion will be studied. This unique combination between experimental and simulation data will allow to have a coherent picture for HA fusion mechanisms. While simulations with segment peptides are relatively fast to calculate, they are still simplified systems of HA. Therefore, simulations with the complete protein will be done to understand, in atomistic detail, the conformational changes in extreme conditions of pH, temperature and ionic strength. Preliminary results already exist. Given that HA mediated membrane fusion is highly dependent on pH, proper simulation of pH effects is key for the success of the work. We are in an unique situation to do these studies, given that the PI of this project is a co¬developer of original methodologies for studying pH effect on proteins (see for example [1]), but most important, a methodology for doing constant pH MD simulations (see for example [2]), allowing an unprecedented physical realism. This methodology is the most adequate for doing the research of this proposal. The PI of this project and head of the Protein Modelling Laboratory of ITQB¬UNL has 20 years of experience in computational structural biology, having worked in a large number of biological and methodological problems. Some of his work was in collaboration with experimentalists, which include the experimental team from IMM (see [3]). The team from IMM has extensive experience in protein/peptide¬membrane interactions, including viral proteins, which is a perfect match for this project. Moreover, the work is based on promising preliminary results, which ensure a positive outcome for the project.

Potential uses/indications

Potential uses/indications



Partner Status: Seeking Partners?


Grant number (QREN, FP7, Eureka, etc)

Grant number (QREN, FP7, Eureka, etc)

Last edited on

2012-06-22 13:53:05

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