The Red Queen hypothesis from a structural perspective: a case study over 30 years of Dengue virus in Brazil

Abstract The interaction between the dengue virus (DENV) and the human dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptor plays a crucial role in viral entry and infection. Understanding the dynamics of this interaction and its evolution over time is essential for comprehending the host-virus relationship and the emergence of viral strains with increased pathogenicity. In this study, we employed phylogenetic filtering to provide a structural approach to investigate the co-evolutionary patterns between DENV envelope (E) protein and human DC-SIGN receptor throughout the evolutionary history of the virus sampling the sequences available in Brazil for the past 30 years. The obtained complexes of DENV E and DC-SIGN were then subjected to molecular dynamics simulations to examine the atomistic interaction using the MM/GBSA methodology. Our results revealed conserved evolutionary patterns of interaction in the DENV E protein We identified specific amino acid residues in the E protein that showed evidence of positive selection and were potentially involved in the interaction with DC-SIGN. This study provides valuable insights into the co-evolutionary dynamics of DENV and the human DC-SIGN receptor. Understanding the evolutionary arms race between viruses and their hosts is critical for developing effective strategies to combat emerging viral pathogens such as DENV. The findings presented here contribute to our knowledge of DENV pathogenesis and may facilitate the design of novel therapeutic interventions targeting the E protein-DC-SIGN interaction by providing a structural perspective on the evolutionary gains this virus must aquire.