Dados do Trabalho

Título

Interactions between DC-SIGN and the envelope protein from Dengue and Zika viruses: a structural perspective based on molecular dynamics and MM/GBSA analyses

Introdução

Zika virus (ZIKV) and Dengue Virus (DENV) share a lot of similarities, being both flaviviruses and neglected tropical diseases that cause a worldwide burden that is increasing with climate change. Studying the interactions of cell recptors and viruses is essential to further the knowledge and development of ways to prevent and control flaviviral diseases. An important interaction occurs between the envelopeof the two viruses and a protein on the surface of immune cells, called DC-SIGN.

Objetivo (s)

To identify and decompose energetically the interactions both DENV and ZIKV mount with the dendritic cell receptor DC-SIGN

Material e Métodos

We describe this interaction in a structural comparison involving homology modeling of these proteins, guided docking based on deposited crystallography, molecular dynamics of the docked complexes, and for the decomposition of interacting residues we employed an analysis of the surface area accessible by the Generalized Bourne method.

Resultados e Conclusão

The energy minimization and the subsequent NVT and NPT equilibrium steps were successfully conducted and the trajectories were produced until reaching 100 ns for the docked complexes. The solvent-accessible surface area (SASA) of both envelope proteins is very similar, and that of ZIKV showed a slight reduction in SASA after the equilibrium and burn-in period of the simulation. On the other hand, when we analyzed the SASA by residue we noticed that some regions are more exposed in the ZIVK protein than in DENV, namely in the regions of domain I and II, responsible for the interaction with DC-SIGN as previously demonstrated for DENV. Both simulations stabilized quickly with small variations in Root Mean Square Deviation (RMSD - FIGURE 2-C) and interestingly we observed differences in alpha-carbon fluctuations after the simulation was completed. The ED-1 and ED-2 region of the ZIKV envelope showed greater flexibility in the range of residues from 70 to 100 whereas the following regions showed less flexibility compared to the DENV envelope.
We observed in the interaction residue decomposition that DENV strongly interacted with DC-SIGN on residues PHE96, PRO217, and TRP465 whereas ZIKV interacted better with residues ARG80, LEU82, PRO208, and ALA227. In comparison with the literature findings, the DC-SIGN residue PHE313 is responsible for most of the interactions with the envelope of these arboviruses, which was also observed here for DENV

Palavras-chave

Dengue, Zika, Molecular Dynamics, MM/GBSA

Agradecimentos

The authors wish to thank Prof. Carlos Bonafé