文章基本信息

标题：Understanding the Targeting Mechanisms of Multi-Specific Biologics in Immunotherapy with Multiscale Modeling
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作者：Zhaoqian Su ; Bo Wang ; Steven C. Almo 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：12
页码：1-32
DOI：10.1016/j.isci.2020.101835
语种：English
出版社：Elsevier
摘要：SummaryImmunotherapeutics 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.Graphical AbstractDisplay OmittedHighlights•Two proteins are connected by different linkers as a model of bispecific biologics•Conformational dynamics of biologics are captured by microsecond MD simulations•Coarse-grained simulations are used to test binding between biologics and receptors•Biologics with long and flexible linkers are more efficient in targeting receptorsImmunology; Therapeutics