How Nanoscale Protein Interactions Determine the Mesoscale Dynamic Organisation of Membrane Proteins

Duncan, Anna L.; Bandurka, Maximilian A. R.; Chavent, Matthieu; Rassam, Patrice; Song, Wanling; Birkholz, Oliver; Hélie, Jean; Reddy, Tyler; Beliaev, Dmitry; Hambly, Ben; Piehler, Jacob; Kleanthous, Colin; Sansom, Mark S.P.

doi:10.1016/j.bpj.2018.11.1984

Cited by 1 publication

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“…Advances in computational hardware also have facilitated the study of complex biological systems. In the last decade, molecular simulations of biological systems with millions of interacting particles over microsecond to millisecond timescales have been reported [64,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116]. These simulations provide unprecedented insights into the system under investigation and bridge nanoscale data to macroscale experimental results.…”

Section: Need For Computational Modelingmentioning

confidence: 99%

Computational Nanoscopy of Tight Junctions at the Blood–Brain Barrier Interface

Rajagopal

Irudayanathan

Nangia

2019

IJMS

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The selectivity of the blood–brain barrier (BBB) is primarily maintained by tight junctions (TJs), which act as gatekeepers of the paracellular space by blocking blood-borne toxins, drugs, and pathogens from entering the brain. The BBB presents a significant challenge in designing neurotherapeutics, so a comprehensive understanding of the TJ architecture can aid in the design of novel therapeutics. Unraveling the intricacies of TJs with conventional experimental techniques alone is challenging, but recently developed computational tools can provide a valuable molecular-level understanding of TJ architecture. We employed the computational methods toolkit to investigate claudin-5, a highly expressed TJ protein at the BBB interface. Our approach started with the prediction of claudin-5 structure, evaluation of stable dimer conformations and nanoscale assemblies, followed by the impact of lipid environments, and posttranslational modifications on these claudin-5 assemblies. These led to the study of TJ pores and barriers and finally understanding of ion and small molecule transport through the TJs. Some of these in silico, molecular-level findings, will need to be corroborated by future experiments. The resulting understanding can be advantageous towards the eventual goal of drug delivery across the BBB. This review provides key insights gleaned from a series of state-of-the-art nanoscale simulations (or computational nanoscopy studies) performed on the TJ architecture.

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