Samsonov Sergey A, Marcisz Mateusz P
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland.
Handb Exp Pharmacol. 2025;288:131-153. doi: 10.1007/164_2025_741.
Glycosaminoglycans (GAGs), linear anionic periodic polysaccharides, play pivotal roles in various biologically relevant processes within the extracellular matrix (ECM). These processes encompass cell development, proliferation, signaling, ECM assembly, coagulation, and angiogenesis. GAGs perform their functions through their interactions with specific protein partners, rendering them attractive targets for regenerative medicine and drug design. However, the molecular mechanisms governing protein-GAG interactions remain unclear. Classical structure determination techniques face significant challenges when dealing with protein-GAG complexes. This is due to GAGs' unique properties, including their extensive length, flexibility, periodicity, symmetry, multipose binding, and the high heterogeneity of their sulfation patterns constituting the "sulfation code." Consequently, only a limited number of experimental protein-GAG structures have been elucidated. Hence, theoretical approaches are particularly promising in deciphering the code for understanding the structure-function relationship of these complex molecules. In this chapter, we focus on the particularities, challenges, and advances of computational methods such as molecular docking, molecular dynamics, and free-energy calculations when applied to GAG-containing systems. These computational approaches offer valuable insights into the enigmatic world of protein-GAG interactions, paving the way for their enhanced understanding and potential therapeutic applications.
糖胺聚糖（GAGs）是线性阴离子周期性多糖，在细胞外基质（ECM）内的各种生物学相关过程中发挥关键作用。这些过程包括细胞发育、增殖、信号传导、ECM组装、凝血和血管生成。GAGs通过与特定蛋白质伙伴的相互作用来履行其功能，使其成为再生医学和药物设计的有吸引力的靶点。然而，控制蛋白质 - GAG相互作用的分子机制仍不清楚。在处理蛋白质 - GAG复合物时，经典的结构测定技术面临重大挑战。这是由于GAGs具有独特的性质，包括其长度长、灵活性高、周期性、对称性、多姿势结合以及构成“硫酸化密码”的硫酸化模式的高度异质性。因此，仅阐明了有限数量的实验性蛋白质 - GAG结构。因此，理论方法在解读密码以理解这些复杂分子的结构 - 功能关系方面特别有前景。在本章中，我们重点关注诸如分子对接、分子动力学和自由能计算等计算方法应用于含GAG系统时的特殊性、挑战和进展。这些计算方法为蛋白质 - GAG相互作用的神秘世界提供了有价值的见解，为增进对它们的理解和潜在治疗应用铺平了道路。
