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Summary: Immunotherapeutics are frequently associated with adverse side effects due to the elicitation of global immune modulation. To lower the risk of these side effects, recombinant DNA technology is employed to enhance the selectivity of cell targeting by genetically fusing different biomolecules, yielding new species referred to as multi-specific biologics. The design of new multi-specific biologics is a central challenge for the realization of new immunotherapies. To understand the molecular determinants responsible for regulating the binding between multi-specific biologics and surface-bound membrane receptors, we developed a multiscale computational framework that integrates various simulation approaches covering different timescales and spatial resolutions. Our model system of multi-specific biologics contains two natural ligands of immune receptors, which are covalently tethered by a peptide linker. Using this method, a number of interesting features of multi-specific biologics were identified. Our study therefore provides an important strategy to design the next-generation biologics for immunotherapy.