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Motivation 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.Results Using homology modeling 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 dimerization mechanism and provide insight into the dynamic behavior of its flexible domains under physiological conditions. We estimated the energy required to disrupt the non-covalent interactions linking LRP1's alpha and beta chains to be 180 +/- 2 kB T. MD simulations further highlight the fundamental role of glycans in stabilizing the dimeric quaternary structure by increasing intra-dimer contacts. The resulting structural models also provide experimentally testable estimates of LRP1 size, domain organization, 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.Availability and implementation The monomeric and dimeric LRP1 models are available in ModelArchive under the accession codes ma-k8036 and ma-ubwf7, respectively.

JTD Keywords: Affinity, Binding, Calcium, Domain, Dynamics, Lrp1, Software news

Efficient drug delivery across the blood–brain barrier (BBB) remains a significant obstacle in treating central nervous system (CNS) disorders. This review provides an in-depth analysis of the structural and molecular mechanisms underlying BBB integrity and its functional properties. We detail the role of key cellular and molecular components that regulate selective molecular transport across the barrier, alongside a description of the current therapeutic approaches for brain drug delivery, including those leveraging receptor-mediated transcytosis. Emphasis is placed on multivalency-based strategies that enhance the specificity of nanoparticle targeting and improve transport efficacy across the BBB. Additionally, we discuss the added value of integrating mathematical and computational models with experimental validation for accelerating BBB-targeted delivery systems optimisation.

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