Understanding the binding sites within proteins is vital for determining their functional properties including the host–virus interactions. Therefore, to meet the pressing demand for rapid identification of these binding sites, fast computational prediction techniques have become essential. The recently developed method EquiPPIS enables accurate and scalable prediction of generalized, partner-independent protein–protein interaction sites for a wide range of proteins and thus can deepen our understanding of viral replication. The predicted interaction sites within these proteins can guide us how to disrupt these viral replications, offering rapid antiviral strategies that are applicable to multiple (+)RNA viruses. Here, we present the detailed procedures of protein–protein interaction site prediction by EquiPPIS and its application in studying viral replication.