Raghu

Multiscale Simulations and Cryo-Electron Microscopy Reveal the Transition Pathway of Dengue Virus-like Particle Nanoassembly Dengue virus (DENV) continues to impose a global health burden, and virus-like particles (VLPs) are promising vaccine candidates, owing to their ability to elicit broadly neutralizing antibodies. However, the lack of nanoscale structural insights into the VLP maturation process has limited rational engineering. Here, we report the cryo-electron microscopy (cryo-EM) structure of immature DENV serotype 2 VLPs, revealing prM–E spikes arrayed on a T = 1 shell, consistent with mature DENV-2 VLPs and distinct from the virion, which exhibits a T = 3 icosahedral lattice. To connect the experimentally determined immature and mature endpoint structures, we employed a multiscale molecular dynamics (MD) framework to assess sterically feasible transition pathways. The simulations support the steric feasibility of a sliding-rotating rearrangement in which trimeric prM–E spikes reorganize into flat E dimers (E–E) without clashes. In virions, trimers reorganize into extended rafts of three parallel E dimers, whereas in VLPs, which lack the long-range symmetry and geometric constraints of the T = 3 lattice, maturation proceeds via a less extensive rearrangement in which neighboring monomers form small triangular clusters of three dimers. In addition, the simulations reveal pronounced lipid core mobility during maturation, including transient and spatially localized lipid protrusion events that preferentially occur near regions undergoing protein rearrangement, consistent with a potential role for dynamic membrane remodeling in accommodating maturation-associated structural changes. We also established a stable Chinese hamster ovary (CHO-K1) producer cell line, enabling efficient production of immature DENV serotype 2 VLPs. Together, this work defines a structure-dynamics framework that links steric feasibility, membrane composition, and particle stability and outlines process-relevant, testable hypotheses to inform future engineering of dengue VLPs that may ultimately guide vaccine design.

Excited to share our latest publication in ACS Nano! Using cryo-EM and multiscale MD simulations, we uncover the nanoscale maturation pathway of dengue VLPs, revealing how glycoprotein and lipid rearrangements govern particle stability and assembly.

pubs.acs.org/doi/full/10....

An integrative approach to rational engineering of dengue virus-like particles Using multiscale simulations and experimental validation, this study uncovers how envelope protein-lipid interactions govern dengue virus-like particle (VLP) stability, secretion, and immunogenicity. ...

Our latest work in Cell Reports Physical Science,
We engineered dengue virus-like particles with enhanced secretion & stability — advancing next-gen VLP-based dengue vaccine development.
#Dengue #VaccineDesign #VirusLikeParticles
www.cell.com/cell-reports...

Structural flexibility in the ordered domain of the dengue virus strain 2 capsid protein is critical for chaperoning viral RNA replication - Cellular and Molecular Life Sciences Viral replication necessitates intricate nucleic acid rearrangements, including annealing and strand displacement to achieve the viral RNA functional structure. Often a single RNA chaperone performs t...

In our latest work on dengue virus (DENV) nucleocapsid assembly, we combine single-molecule FRET and molecular dynamics simulations to reveal mechanistic insights into the RNA chaperone activity of the DENV Capsid (C) protein.
link.springer.com/article/10.1...

Using AI to prepare for academic interviews – don’t trade authenticity for polish | EMBO reports EMBO Press is an editorially independent publishing platform for the development of EMBO scientific publications.

My latest column in EMBO Reports @emboreports.org , co-authored with Will Ratcliff @wcratcliff.bsky.social : "Using AI to prepare for academic interviews – don’t trade authenticity for polish." www.embopress.org/doi/full/10....

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