高合作二价大分子设计的介观计算方法
Mesoscale computational protocols for the design of highly cooperative bivalent macromolecules
摘要：
在过去的十年中，人们对设计和生产新型多价分子的兴趣迅速增加，这些分子是对抗癌症和传染病的常规抗体的有力替代品。然而，尽管广泛接受大尺度柔性（$10-100$ nm）和自由/约束动力学（100 ns $- μ$ s）控制这种新型分子的活性，但在优化关键特征（例如结合协同性（a.k.a.亲合力）。在这项研究中，我们介绍了不同的粗粒度模型的聚合物连接，两个纳米体复合分子，奠定了物理基础的一个彻底的计算药物设计协议在中尺度的目的。我们表明，计算适当的平均力的潜力，使人们能够理解的性质，范围和强度的热力学力，支配自由和壁系分子的运动。此外，我们开发了一个简单的计算策略，以量化的接触/解离动力学之间的自由端的壁系分子和表面，在结合协同性的根源。这个过程允许一个查明的作用，内部的灵活性和弱非特异性相互作用的动力学常数的NB壁遇到和解离。最后，我们量化了罕见事件的作用和权重，这些事件预计将在现实生活中发挥重要作用，例如在免疫突触中，结合动力学可能受波动影响。
英文摘要：
The last decade has witnessed a swiftly increasing interest in the design and production of novel multivalent molecules as powerful alternatives for conventional antibodies in the fight against cancer and infectious diseases. However, while it is widely accepted that large-scale flexibility ($10-100$ nm) and free/constrained dynamics (100 ns $- μ$s) control the activity of such novel molecules, computational strategies at the mesoscale still lag behind experiments in optimizing the design of crucial features, such as the binding cooperativity (a.k.a. avidity). In this study, we introduced different coarse-grained models of a polymer-linked, two-nanobody composite molecule, with the aim of laying down the physical bases of a thorough computational drug design protocol at the mesoscale. We show that the calculation of suitable potentials of mean force allows one to apprehend the nature, range and strength of the thermodynamic forces that govern the motion of free and wall-tethered molecules. Furthermore, we develop a simple computational strategy to quantify the encounter/dissociation dynamics between the free end of a wall-tethered molecule and the surface, at the roots of binding cooperativity. This procedure allows one to pinpoint the role of internal flexibility and weak non-specific interactions on the kinetic constants of the NB-wall encounter and dissociation. Finally, we quantify the role and weight of rare events, which are expected to play a major role in real-life situations, such as in the immune synapse, where the binding kinetics is likely dominated by fluctuations.
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