IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Influenza A protein M1 dimerization and binding to a prototype membrane
Autor/es:
DI LELLA, SANTIAGO; ANDREAS HERRMANN
Lugar:
Cagliari
Reunión:
Simposio; 7th International Theoretical Biophysics Symposium; 2015
Resumen:
Influenza A is a negative stranded RNA virus with a genome segmented in eight fragments, each encoding for at least one viral protein. From them, the matrix protein M1 appears to be the determinant of virus structure, and is involved in the assembly and budding of new viral particles, especially during the formation of a membrane-associated capsid that encapsulates the viral genome.[1] The current model suggest that binding of M1 to the cytoplasmic tails of hemagglutinin and neuraminidase, two other viral proteins, induces M1 polymerization.[2] However, recent evidence provided that M1 multimerizes upon binding to the plasma membrane in the absence of other viral proteins, but there is still controversy on the state of aggregation in solution and the factors favoring its multimerization in the presence of the membrane.[3] Consisting on a 252 polypeptide chain, crystallographic studies [4] of the N-terminal domain of M1 (a.a. 2-158, M1n) revealed  two interfaces  able to self-assemble into double M1 ribbons leading to a nanotube-like, helical structure. However, the a self-assembly model lacked the structure of the C-terminal domain of M1 (a.a. 165-252, M1c). Such a complete model has been recently proposed in our group.[4] However, no dynamic evaluation or further tests were performed for such a model. In this work, we employed molecular dynamics simulations schemes in order to provide insights into the structure and stability of M1 monomer and dimer, and into the interaction of the M1 with a model membrane. On a first approach, 100 ns all-atom molecular dynamics simulations were performed of both a monomer and dimer of the M1 protein and the M1c domain in explicit TIP3P water model. Structural and energetic computation, as well as an essential mode analysis were performed. Our simulations show that the M1c domain host the major contribution in protein first-weighted essential modes, presumibily acting as an entropy reservoir. On a second approach, and in a search to evaluate the involvement of specific domains favoring contacts, a steered molecular dynamic scheme was used to study M1 interaction with the model membrane. For this purpose, a DOPC-DOPS in a 70:30 proportion bilayer membrane was modeled. Then, several assemblies consisting of either the M1c domain or the whole M1 protein in a set of different rotational orientation of the protein with respect to the bilayer were constructed performing rigid body rotations. The pulling reaction coordinate was defined as the distance between the center of mass of both the protein and the bilayer. A constant force along this reaction coordinate was applied for each case. This computational experiment allowed to evaluate different binding configuration. Results show that M1c interaction with the membrane is energetically favorable in a configuration compatible with the dimer proposed structure. Results are then discussed and compared with experimental data.