A computational analysis of the glycoprotein LRP1 structure and the role of glycans as quaternary glue

The low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in development and transport across the blood-brain barrier (BBB), yet until now, its molecular architecture remained unresolved due to the absence of an experimentally determined structure. Using homology modeling and neural network-based structure prediction algorithms, complemented with molecular dynamics (MD) simulations, we propose a comprehensive model of LRP1 structures. We observe a natural dimerization mechanism and provide insight into the dynamic behavior of its flexible domains under physiological conditions. We investigated the stability of non-covalent interactions keeping LRP1’s α and β chains linked together, and found the energy required to break the link is 180±2 kT. The MD characterization highlights the fundamental role of glycans in the creation of LRP1’s quaternary structure, increasing the number of intra-dimeric contacts. This study opens new avenues for targeted drug design strategies, enhancing our molecular understanding of LRP1’s receptor-mediated transport in the brain and the key mediation of glycosylation in protein-protein interactions.