(376z) Development of a New Computational Tool to Study Protein Assembly at the Blood-Brain Barrier Interface

Transport of molecules to the brain from the neurovasculature, across the blood-brain barrier (BBB) interface, occurs via two major pathways—paracellular and transcellular. The paracellular pathway is passively regulated by transmembrane proteins that interact with each other to form physical barriers called the tight junctions. The tight junctions exhibit charge and size selectivity depending on the structure of the interacting proteins. It is, therefore, important to understanding the molecular-level interactions that constitute the tight junction architecture, especially at the BBB interface to enable the design of drug delivery modalities to treat neurological diseases. Experimental investigation of membrane protein association is challenging due to the hydrophobic membrane environment surrounding the proteins. Although numerous computational methods have been put forth to overcome this challenge, a comprehensive method capturing details of all possible states of protein interactions is yet to be developed. In this work, we present the development of a—new tool—that provides quantitative estimates of membrane protein association for generating a comprehensive Protein Association Energy Landscape (PANEL). The PANEL is a computationally inexpensive approach to producing energy profiles for a wide range of proteins. We have used our method to show the association of membrane proteins responsible for the selectivity of the blood-brain tight junctions.