title: Membrane undulation induced by NS4A of Dengue virus: a molecular dynamics simulation study.
abstract: Nonstructural protein 4A (NS4A) of Dengue virus (DENV) is a membrane protein involved in rearrangements of the endoplasmic reticulum membrane that are required for formation of replication vesicles. NS4A is composed most likely of three membrane domains. The N- and C-terminal domains are supposed to traverse the lipid membrane whereas the central one is thought to reside on the membrane surface, thus forming a u-shaped protein. All three membrane domains are proposed to be helical by secondary structure prediction programs. After performing multi nanosecond molecular dynamics (MD) simulations at various temperatures (300, 310, and 315.15 K) with each of the individual domains, they are used in a docking approach to define putative association motifs of the transmembrane domains (TMDs). Two structures of the u-shaped protein are generated by separating two assembled TMDs linking them with the membrane-attached domain. Lipid undulation is monitored with the structures embedded in a fully hydrated lipid bilayer applying multiple 200 ns MD simulations at 310 K. An intact structure of the protein supports membrane undulation. The strong unwinding of the helices in the domain-linking section of one of the structures lowers its capability to induce membrane curvature. Unwinding of the link region is due to interactions of two tryptophan residues, Trp-96 and 104. These results provide first insights into the membrane-altering properties of DENV NS4A.
authors: a Institute of Biophotonics, School of Biomedical Science and Engineering, National Yang-Ming University and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University , 155, Li-Non St., Sec. 2, Taipei , 112 , Taiwan .
authors: Meng-Han
authors: MH
authors: Lin
authors: Hao-Jen
authors: HJ
authors: Hsu
authors: Ralf
authors: R
authors: Bartenschlager
authors: Wolfgang B
authors: WB
authors: Fischer
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry*; D003716:Dengue Virus / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D017361:Viral Nonstructural Proteins
keywords: Dengue virus; NS4A; assembly; membrane protein; membrane undulation; molecular dynamics simulations