Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.
Methods Mol Biol. 2023;2552:125-139. doi: 10.1007/978-1-0716-2609-2_6.
This chapter describes the application of constrained geometric simulations for prediction of antibody structural dynamics. We utilize constrained geometric simulations method FRODAN, which is a low computational complexity alternative to molecular dynamics (MD) simulations that can rapidly explore flexible motions in protein structures. FRODAN is highly suited for conformational dynamics analysis of large proteins, complexes, intrinsically disordered proteins, and dynamics that occurs on longer biologically relevant time scales that are normally inaccessible to classical MD simulations. This approach predicts protein dynamics at an all-atom scale while retaining realistic covalent bonding, maintaining dihedral angles in energetically good conformations while avoiding steric clashes in addition to performing other geometric and stereochemical criteria checks. In this chapter, we apply FRODAN to showcase its applicability for probing functionally relevant dynamics of IgG2a, including large-amplitude domain-domain motions and motions of complementarity determining region (CDR) loops. As was suggested in previous experimental studies, our simulations show that antibodies can explore a large range of conformational space.
本章介绍了约束几何模拟在预测抗体结构动力学中的应用。我们利用约束几何模拟方法 FRODAN，这是一种计算复杂度低于分子动力学（MD）模拟的方法，可以快速探索蛋白质结构中的柔性运动。FRODAN 非常适合于大蛋白、复合物、内源性无序蛋白的构象动力学分析，以及通常无法通过经典 MD 模拟访问的更长生物学相关时间尺度上的动力学。该方法在保留真实共价键的情况下，在全原子尺度上预测蛋白质动力学，同时保持能量良好构象中的二面角，避免立体冲突，并执行其他几何和立体化学标准检查。在本章中，我们应用 FRODAN 来展示其在探测 IgG2a 功能相关动力学方面的适用性，包括大振幅的结构域-结构域运动和互补决定区（CDR）环的运动。正如之前的实验研究所表明的，我们的模拟表明抗体可以探索大范围的构象空间。
