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

Abstract

The low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in development and transport across the blood-brain barrier (BBB), yet its molecular architecture has remained unresolved due to the absence of an experimentally determined structure. Using homology modelling and neural network-based structure prediction algorithms, complemented with molecular dynamics (MD) simulations, we propose atomistic models of both monomeric and dimeric LRP1 forms. The simulations reveal a plausible dimerisation mechanism and provide insight into the dynamic behaviour of its flexible domains under physiological conditions. We estimated the energy required to disrupt the non-covalent interactions linking LRP1's α and β chains to be 180±2 kBT. MD simulations further highlight the fundamental role of glycans in stabilising the dimeric quaternary structure by increasing intra-dimer contacts. The resulting structural models also provide experimentally testable estimates of LRP1 size, domain organisation, and interface stability that may guide future imaging and mutagenesis studies. This study enhances our molecular understanding of LRP1-mediated transport across the BBB and the role of glycosylation in protein-protein interactions, opening new avenues for targeted drug design strategies. The monomeric and dimeric LRP1 models are available in ModelArchive under the accession codes ma-k8036 and ma-ubwf7, respectively. Supplementary data are available online.