(330a) Developing Multiscale Models of the Blood-Brain Barrier Interface for the Treatment of Alzheimer's Disease

The blood-brain barrier (BBB) is a selective permeability barrier that impedes the influx of potentially harmful blood-borne chemicals from entering the brain. Specialized physical barriers called tight junctions, formed by the endothelial cells lining the brain, act as intercellular gatekeepers in regulating the passive diffusion of molecules and ions into the brain. Although the BBB is vital for neurological functions, its selective permeability is a deterrent in getting drug molecules into the brain. The tight junction selectivity obstructs effective treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's, which disproportionately affect older individuals. Since the segment of the US population older than 65 is expected to increase by 50% by 2030, the cost of care of these diseases is on the order of billions of dollars per year, finding ways to enable drug molecules to cross the BBB is urgently needed.
The claudin family of membrane proteins plays a crucial role in forming the tight junctions. Experimental imaging methods have successfully achieved high-resolution images of the self-assembled claudin strands in vitro. However, these length scales do not provide molecular-level resolution between interacting protein partners. Several computational studies have shown detailed molecular-level interactions, but high computational costs limited the analysis to small lengths and timescales than those observed experimentally. To bridge this knowledge gap, we developed two sets of computational algorithms: Protein Association Energy Landscape (PANEL) to obtain protein dimer interaction stabilities; and Tight Junction Strand Prediction Protocol (TJ-straPP) to predict the TJ strand architecture. Based on the claudin-claudin dimer stability and probabilistic data generated from PANEL, the TJ-StraPP algorithm predicts TJ strands' structure made up of thousands of claudin proteins reaching up to micron-scale output while preserving the atomistic-level details of the assembled claudin strands.
This work is enabling the discovery of sustainable, non-evasive, and thermodynamically favorable pathways to transport small drug molecules into the brain. This talk will provide an overview of the challenge blood-brain barrier and how multiscale simulations are contributing to the development of new treatment strategies for Alzheimer's disease.