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A variety of amino acid substitutions in the NS3-4A protease of the hepatitis C virus lead to protease inhibitor (PI) resistance. Many of these significantly impair the replication fitness of the resistant variants in a genotype- and subtype-dependent manner, a critical factor in determining the probability with which resistant variants will persist. However, the underlying molecular mechanisms are unknown. Here, we present a novel residue-interaction network approach to determine how near-neighbor interactions of PI resistance mutations in NS3-4A can impact protease functional sites dependent on their genomic background. We constructed subtype-specific consensus residue networks for subtypes 1a and 1b from protease structure ensembles combined with biological properties of protein residues and evolutionary amino acid conservation. By applying local and global network topology analysis and visual exploration, we characterize PI resistance-associated sites and outline differences in near-neighbor interactions. We find local residue-interaction patterns and features at protease functional sites that are subtype specific. The noncovalent bonding patterns indicate higher fitness costs conferred by PI resistance mutations in a subtype 1b genomic background and explain the prevalence of Q80K and R155K in subtype 1a. Based on local residue interactions, we predict a subtype-specific role for the protease residue NS3–Q80 in molecular mechanisms related to the assembly of infectious virus particles that is supported by experimental data on the capacity of Q80K variants to replicate and produce infectious virus in subtype 1a and 1b cell culture. Unlabelled Image • A novel graph-based approach is applied to characterize multiple NS3-4A structure models. • Residue-interaction patterns at PI resistance sites are HCV subtype specific. • PI resistance sites are closer to NS3-4A protease functional sites in subtype 1b than 1a. • NS3–Q80K impairs infectious virus particle assembly specifically in subtype 1b. • This paper highlights subtype-specific molecular mechanisms in RAV persistence. [ABSTRACT FROM AUTHOR]

Background: An important aspect of studying the relationship between protein sequence, structure and function is the molecular characterization of the effect of protein mutations. To understand the functional impact of amino acid changes, the multiple biological properties of protein residues have to be considered together. Results: Here, we present a novel visual approach for analyzing residue mutations. It combines different biological visualizations and integrates them with molecular data derived from external resources. To show various aspects of the biological information on different scales, our approach includes one-dimensional sequence views, threedimensional protein structure views and two-dimensional views of residue interaction networks as well as aggregated views. The views are linked tightly and synchronized to reduce the cognitive load of the user when switching between them. In particular, the protein mutations are mapped onto the views together with further functional and structural information. We also assess the impact of individual amino acid changes by the detailed analysis and visualization of the involved residue interactions. We demonstrate the effectiveness of our approach and the developed software on the data provided for the BioVis 2013 data contest. Conclusions: Our visual approach and software greatly facilitate the integrative and interactive analysis of protein mutations based on complementary visualizations. The different data views offered to the user are enriched with information about molecular properties of amino acid residues and further biological knowledge. [ABSTRACT FROM AUTHOR]