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.