Membrane undulation induced by NS4A of Dengue virus: a molecular dynamics simulation study

Area of Science:

• Virology
• Structural Biology
• Biophysics

Background:

• Nonstructural protein 4A (NS4A) is essential for Dengue virus (DENV) replication.
• NS4A is a membrane protein that induces endoplasmic reticulum membrane rearrangements.
• NS4A is predicted to have three membrane-associated domains forming a u-shaped structure.

Purpose of the Study:

• To investigate the structural dynamics and membrane-altering properties of DENV NS4A.
• To elucidate the role of NS4A's membrane domains in viral replication vesicle formation.
• To understand how NS4A induces membrane curvature.

Main Methods:

• Multi-nanosecond molecular dynamics (MD) simulations of individual NS4A domains at various temperatures.
• Docking approaches to identify association motifs of transmembrane domains (TMDs).
• Longer MD simulations (200 ns) of NS4A embedded in lipid bilayers to monitor lipid undulation and membrane curvature.

Main Results:

• Two distinct structures of the u-shaped NS4A protein were generated.
• Intact NS4A structures effectively support membrane undulation.
• Unwinding of helices in the linker region, influenced by Trp-96 and Trp-104, reduced the protein's ability to induce membrane curvature.

Conclusions:

• DENV NS4A possesses membrane-altering capabilities crucial for viral replication.
• The structural integrity and specific residue interactions within NS4A dictate its membrane curvature-inducing function.
• These findings offer initial insights into the biophysical mechanisms of DENV NS4A in modulating host cell membranes.