Influenza A protein M1 binding to a bilayer membrane as studied by molecular dynamics simulations

DI LELLA, SANTIAGO; ANDREAS HERRMANN

Innsbruck

Otro; Advanced Lecture Course on System Biology; 2016

p { margin-bottom: 0.1in; direction: ltr; color: rgb(0, 0, 0); line-height: 120%; text-align: left; }p.western { font-family: "Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "宋体"; font-size: 12pt; }p.ctl { font-family: "Times New Roman",serif; font-size: 12pt; }Influenza A is a negative stranded RNA virus with a genome segmentedin eight fragments, each encoding for at least one viral protein.From them, the matrix protein M1 appears to be the determinant ofvirus structure, and is involved in the assembly and budding of newviral particles, especially during the formation of amembrane-associated capsid that encapsulates the viral genome.[1] Thecurrent model suggest that binding of M1 to the cytoplasmic tails ofhemagglutinin and neuraminidase, two other viral proteins, induces M1polymerization.[2] However, recent evidence provided that M1multimerizes upon binding to the plasma membrane in the absence ofother viral proteins, but there is still controversy on the state ofaggregation in solution and the factors favoring its multimerizationin the presence of the membrane.[3] Consisting on a 252 polypeptidechain, crystallographic studies [4] of the N-terminal domain of M1(a.a. 2-158, M1n) revealed two interfaces able to self-assembleinto double M1 ribbons leading to a nanotube-like, helical structure.However, the a self-assembly model lacked the structure of theC-terminal domain of M1 (a.a. 165-252, M1c). Such a complete modelhas been recently proposed in our group.[4] However, no dynamicevaluation or further tests were performed for such a model. In this work, we employed molecular dynamics simulations schemes inorder to provide insights into the structure and stability of M1monomer and dimer, and into the interaction of the M1 with a modelmembrane. On a first approach, 100 ns all-atom molecular dynamicssimulations were performed of both a monomer and dimer of the M1protein and the M1c domain in explicit TIP3P water model. Structuraland energetic computation, as well as an essential mode analysis wereperformed. Our simulations show that the M1cdomain host the major contribution in protein first-weightedessential modes, presumibily acting as an entropy reservoir. On a second approach, and in a search to evaluate the involvement ofspecific domains favoring contacts, a steered molecular dynamicscheme was used to study M1 interaction with the model membrane. Forthis purpose, a DOPC-DOPS in a 70:30 proportion bilayer membrane wasmodeled. Then, several assemblies consisting of either the M1c domainor the whole M1 protein in a set of different rotational orientationof the protein with respect to the bilayer were constructedperforming rigid body rotations. The pulling reaction coordinate wasdefined as the distance between the center of mass of both theprotein and the bilayer. A constant force along this reactioncoordinate was applied for each case. This computational experimentallowed to evaluate different binding configuration. Results showthat M1c interaction with the membrane is energetically favorable ina configuration compatible with the dimer proposed structure. Resultsare then discussed and compared with experimental data.