Genetic Diversity and Adaptation of Mayaro Virus (MAYV) to Different Hosts: Computational Analysis of Mutations in the nsP1 protein

Mayaro virus (MAYV) is an emerging arbovirus with epidemic potential. As an RNA virus, it has high genetic variability, driven by distinct selective pressures imposed by its vectors (invertebrates) and hosts (vertebrates). Recent studies by our research group have evaluated the genetic variability and adaptive dynamics of the virus using in vitro models in inter-host and intra-host transmission cycles. For the inter-host cycles, human (HFF1) and Aedes aegypti (Aag2) cells were used. For the intra-host cycles, the same cell types were subjected to sequential passages. After each passage, the virus was subjected to sequencing by next-generation platforms (NGS) to analyze the frequency and emergence of mutations. Key mutations arose at high frequency in the NSP1 protein of MAYV, such as: W456G (80%) in the inter-host HFF1 cycle, W456G (42%) and W456R (56%) in the intra-host AAG2 cycle. Based on these findings, the nsP1 protein was modeled via AlphaFold2 from its FASTA sequences. The W456G and W456R mutations occur in a flexible loop of the nsP1 protein, close to the Zn⁺ coordination site, with W456 being a relevant residue that contributes to local stability. To investigate the structural and functional impacts of mutations in the nsP1 protein, the wild-type and mutated systems will be subjected to molecular dynamics simulations (300 ns). The analysis will include measures of global stability (RMSD), flexibility per residue (RMSF), hydrogen bond patterns, secondary structure evolution, and calculation of free bond-free energy by MM-GBSA. Computational tracking of these changes offers a solid basis for understanding the adaptive role of mutations in different hosts, supporting molecular surveillance and MAYV control strategies.