Computational Modeling of the Dengue Virus Envelope and Membrane Protein Complex Maturation Pathway

ABSTRACT Dengue virus (DENV) maturation is an intricate process with notable conformational alterations of the virus envelope (E)‐membrane (M) protein complex. The virus is not infective unless this maturation has taken place. Insight into the mechanism of these conformational transitions is imperative in designing effective targeted antiviral therapy. We utilized here a suite of molecular dynamics (MD) simulations, Quasi Markov state models (QMSM), and targeted MD simulations in order to reproduce the dengue virus E‐M heterodimer's pathway for the conformation change through maturation of the protein complex from its immature state into a mature one. We utilized targeted MD simulations for driving sampling of the pathway for conformational change in order to produce greater understanding in protein's dynamics. Key intermediate conformations were examined by using extensive MD simulations to probe the conformational landscape of the E‐M heterodimer, and then a QMSM was built to embed the transition dynamics between major conformational states. The findings reveal some key intermediate states involved in the maturation process, presenting new insights into the protein's structural rearrangements. This study provides important information into the mechanistic and structural aspects of dengue virus maturation.