Abstract
ABSTRACT The non-structural protein 1 (NS1), a viral toxin, is linked to serious consequences of dengue. Given its crucial role in the viral life cycle, NS1 has been a primary target for antiviral drug development. This study elucidates the mechanistic impact of specific NS1 mutations, V220D and A248V, identified by Tan and colleagues as potential inhibitors of viral replication. We developed an integrated computational framework to analyze these mutations relative to the native NS1 protein. Using conventional all-atom molecular dynamic simulations followed by site-directed in silico mutagenesis, significant alterations in protein structure were observed. Conformational ensembles over time showed average backbone deviations of 0.44 nm and 0.43 nm for V220D and A248V, respectively, compared to 0.37 nm for the wild type. Residue-wise fluctuations were higher in A248V compared to both wild type and V220D systems. Mutation-induced disruptions in the hydrogen bond network and altered protein structure graphs were also revealed. Principal component analysis and free energy landscape assessments showed the wild-type protein had a more constrained and stable conformation, whereas the mutants displayed scattered energy contours, suggesting reduced structural stability. This comprehensive assessment provides deep insight into the structural impact of NS1 mutations, informing future efforts in antiviral drug development targeting NS1.
Published Version
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