Viruses are enthusiastically studied due to the great impact that these organisms can have on human health. Computational approaches can contribute offering tools that can shed light on important molecular mechanisms that help to design new diagnostic procedures. Several cellular processes between the immune-host system and the pathogenic organism are dependent on specific intermolecular interactions. In this study, we evaluated theoretical approaches to understand some properties of the antigen−antibody interactions considering the titratable properties of all ionizable residues of the nonstructural viral protein 1 (NS1) of the West Nile virus (WNV) and the Zika virus (ZIKV). Constant-pH Monte Carlo simulations were performed to estimate electrostatic properties such as the pK a shifts (ΔpK a ). We proposed an alternative criterion for the discrimination of antigenic residues based on ΔpK a s. Our outcomes were analyzed by an evaluation of the sensitivity and specificity through a receiver operating characteristic (ROC). As a starting point, we used the known crystallographic structure for the complex of NS1 WNV(176−352) and the specific antibody 22NS1 (PDB ID 4OII) to differentiate the residues belonging to that interface. With an optimal threshold for the absolute value of the pK a shifts, we found that is possible to predict antigenic epitopes reproducing the interfaces as defined by the X-ray structure. After this validation, we evaluated theoretical predictions based on protein− protein (PP) complexation simulations. From them, we observe amino acids with an antigenic potential and defined the optimum threshold that was applied for two strains of ZIKV (i.e., Uganda and Brazil). Several ionizable residues with antigenic capacity were identified. This is favorably related to some studies that show the high immunogenicity of secreted NS1. This approach opens up an important discussion about what are termed here "electrostatic epitopes" and how they work as an important reference in the paratope−epitope interaction for viral systems.

The flavivirus genus has several organisms responsible for generating various diseases in humans. Recently, especially in tropical regions, Zika virus (ZIKV) has raised great health concerns due to the high number of cases affecting the area during the last years that has been accompanied by a rise in the cases of the Guillain–Barré syndrome and fetal and neonatal microcephaly. Diagnosis is still difficult since the clinical symptoms between ZIKV and other flaviviruses (e.g., dengue and yellow fever) are highly similar. The understanding of their common physicochemical properties that are pH-dependent and biomolecular interaction features and their differences sheds light on the relation strain-virulence and might suggest alternative strategies toward differential serological diagnostics and therapeutic intervention. Due to their immunogenicity, the primary focus of this study was on the ZIKV nonstructural proteins 1 (NS1). By means of computational studies and semiquantitative theoretical analyses, we calculated the main physicochemical properties of this protein from different strains that are directly responsible for the biomolecular interactions and, therefore, can be related to the differential infectivity of the strains. We also mapped the electrostatic differences at both the sequence and structural levels for the strains from Uganda to Brazil, which could suggest possible molecular mechanisms for the increase of the virulence of ZIKV in Brazil. Exploring the interfaces used by NS1 to self-associate in some different oligomeric states and interact with membranes and the antibody, we could map the strategy used by the ZIKV during its evolutionary process. This indicates possible molecular mechanisms that can be correlated with the different immunological responses. By comparing with the known antibody structure available for the West Nile virus, we demonstrated that this antibody would have difficulties to neutralize the NS1 from the Brazilian strain. The present study also opens up perspectives to computationally design high-specificity antibodies.

Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.