Department of General and Inorganic Chemistry, University of Parma, Parma, Italy.
Curr Top Med Chem. 2011;11(2):192-210. doi: 10.2174/156802611794863571.
The intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes.
生物大分子的固有动力学是将生物分子系统的结构与其在细胞中的功能联系起来的一个基本属性。在配体-受体识别领域，大量证据揭示了锁钥理论的局限性，需要详细阐述考虑生物分子固有可塑性的模型，例如诱导契合模型或存在预先平衡构象的集合。根据目标系统的性质，配体结合可能与侧链的小局部调整相关，甚至与结构片段、结构域甚至亚基的大尺度运动相关。因此，重现生物分子的固有灵活性已成为分子建模和模拟研究中最具挑战性的问题之一，因为它直接影响我们对结构-功能关系的理解，但即使在虚拟筛选和基于结构的药物发现等领域也是如此。鉴于传统模拟工具的固有局限性，只有通过全原子技术（如分子动力学模拟）才能在高精度水平上再现短时间尺度内发生的事件。然而，更大的结构重排需要使用增强采样方法，这些方法依赖于对生物分子系统或势能表面的修改描述。本综述通过代表性示例说明了结构可塑性在介导配体识别方面的关键作用。此外，它还讨论了一些为表征配体-受体复合物的构象灵活性而开发的最强大的计算工具。
