Predicting selectivity of paracellular pores for biomimetic applications

Rajagopal, Nandhini; Durand, Alejandro J.; Nangia, Shikha

doi:10.1039/c9me00177h

Cited by 8 publications

(9 citation statements)

References 68 publications

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“…Indeed, computational works indicate the potential coexistence of the two pores in the same TJ strands. Coarse-grained MD simulations of self-assembly of Cldn protomers suggest diverse possible cis- dimers arrangements in the strand, all consistent with the units that construct the two pore configurations. ,, Furthermore, the same authors confirmed the formation of similar dimers using the PANEL software to obtain millions of Cldn–Cldn conformations and to analyze the amino acid contact maps. , The results showed the presence of both the Pore I and Pore II structures investigated in this work for Cldn5.…”

Section: Resultssupporting

confidence: 77%

“…The MD simulations presented in ref demonstrate that the Cldn5 Pore II is impermeable to small molecules such as α-D glucose but permissive to water. However, at variance with Pore I, the Pore II model is still limitedly investigated, ,,− and further studies are required to chart its structural and functional hallmarks. Moreover, a detailed investigation of its ionic permeability has not been performed yet, thus hampering a thorough comparison with Pore I.…”

Section: Introductionmentioning

confidence: 99%

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Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood–Brain Barrier Tight Junctions

Berselli

Alberini

Benfenati

et al. 2022

ACS Chem. Neurosci.

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The blood–brain barrier (BBB) strictly regulates the exchange of ions and molecules between the blood and the central nervous system. Tight junctions (TJs) are multimeric structures that control the transport through the paracellular spaces between the adjacent brain endothelial cells of the BBB. Claudin-5 (Cldn5) proteins are essential for TJ formation and assemble into multiprotein complexes via cis-interactions within the same cell membrane and trans-interactions across two contiguous cells. Despite the relevant biological function of Cldn5 proteins and their role as targets of brain drug delivery strategies, the molecular details of their assembly within TJs are still unclear. Two different structural models have been recently introduced, in which Cldn5 dimers belonging to opposite cells join to generate paracellular pores. However, a comparison of these models in terms of ionic transport features is still lacking. In this work, we used molecular dynamics simulations and free energy (FE) calculations to assess the two Cldn5 pore models and investigate the thermodynamic properties of water and physiological ions permeating through them. Despite different FE profiles, both structures present single/multiple FE barriers to ionic permeation, while being permissive to water flux. These results reveal that both models are compatible with the physiological role of Cldn5 TJ strands. By identifying the protein–protein surface at the core of TJ Cldn5 assemblies, our computational investigation provides a basis for the rational design of synthetic peptides and other molecules capable of opening paracellular pores in the BBB.

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Section: Resultssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood–Brain Barrier Tight Junctions

Berselli

Alberini

Benfenati

et al. 2022

ACS Chem. Neurosci.

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“…A series of charged residues K31, K48, D65, E53, and Q63 from each claudin form the pore walls. 35 13.5 ± 0. water experiences a nominal barrier of 1.0 ± 0.01 kJ mol −1 toward the center of the pore, which is insignificant at physiological temperatures. The D65A mutation causes the barrier to increase to 1.9 ± 0.1 kJ mol −1 without adversely affecting the water permeability through the pore.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The pore is widest at the entrance (0.8 ± 0.1 nm) and narrowest in the middle (0.28 ± 0.08 nm), as shown in Figure b. A series of charged residues K31, K48, D65, E53, and Q63 from each claudin form the pore walls . Transport of water experiences a nominal barrier of 1.0 ± 0.01 kJ mol –1 toward the center of the pore, which is insignificant at physiological temperatures.…”

Section: Molecular Transport Through Claudin-2 Porementioning

confidence: 98%

Paracellular Gatekeeping: What Does It Take for an Ion to Pass Through a Tight Junction Pore?

Irudayanathan

Nangia

2020

Langmuir

Self Cite

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Tight junction pores are physiological gatekeepers of paracellular transport in epithelial tissues. Conventionally, tight junction permeability is determined via in vitro electrophysiology measurements; however, the macroscopic readout does not provide molecular-level understanding into the mechanism of ion permeation. Insight into the factors governing selectivity across the paracellular space is just emerging. In this study, we investigated tight junction pores comprising of claudin-2 and claudin-5 proteins that are structurally similar to subnanometer radii but have measurably different in vitro ion permeabilities. To evaluate the mechanistic differences in ion transport across the pores, we computed the free-energy profiles and relative rate constants for the transport of monovalent (Na + , K + , Cl − ) and divalent (Mg 2+ and Ca 2+ ) ions through the pores using replica exchange metadynamics. In claudin-2, we demonstrate how a single residue dictates selective permeability of Na + and K + ions. In claudin-5, we found no clear preference for anion or cation selectivity; thus, pores formed by claudin-5 are indeed barriers to ion permeation. Mutations to claudin-5 that widen the pore's steric radius did not significantly impact pore selectivity, indicating that electrostatics dominate pore selectivity. The key takeaways from this work are as follows: (a) two pores that are similar in diameter and length can have dissimilar ion conductance, (b) existence of a physical pore does not guarantee ion permeability, and (c) the electrostatic environment created by the pore-lining residues dictates the ion conductivity. These mechanistic understandings of the tight junction pores are critical for the interpretation of tight junction physiology.

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“…Coarse grained MD simulations of self-assembly of Cldn protomers suggest diverse possible cis-dimers arrangements in the strand, all consistent with the units that construct the two pore configurations 34,35,40 . Furthermore, the same authors confirmed the formation of similar dimers using the PANEL software to obtain millions of Cldn-Cldn conformations and to analyze the amino acid contact maps 41,63 . The results showed the presence of both the Pore I and Pore II structures investigated in this work for Cldn5.…”

Section: Fe Calculationsmentioning

confidence: 81%

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood-Brain-Barrier Tight-Junctions

Berselli

Alberini

Maragliano

et al. 2022

Preprint

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The blood-brain barrier (BBB) strictly regulates the exchange of ions and molecules between the blood and the central nervous system. The tight junctions (TJs) are multimeric structures that control the transport through the paracellular spaces between adjacent brain endothelial cells of the BBB. Claudin-5 (Cldn5) proteins are essential for the TJ formation. They assemble into multi-protein complexes via cis- interactions within the same cell membrane, and trans-interactions across two contiguous cells. Despite the barrier function of Cldn5 proteins and their role as targets of brain drug delivery strategies, the molecular details of their assembly within TJs are still unclear. Two different structural models have been recently introduced, in which Cldn5 dimers belonging to opposite cells join together to generate paracellular pores. However, a comparison of these models in terms of ionic transport features is still lacking. In this work, we used extended molecular dynamics simulations and free energy calculations to assess the two Cldn5 pore models and investigate the thermodynamic properties of water and physiological ions permeation through them. Despite different FE profiles, both structures present single or multiple FE barriers to ionic permeation, while being permissive to water flux. These results reveal that both models are compatible with the physiological role of Cldn5 TJ strands. By identifying the protein-protein surface at the core of TJ Cldn5 assemblies, our computational investigation provides a basis for the rational design of synthetic peptides and other molecules capable of opening paracellular pores in the BBB.

show abstract

Predicting selectivity of paracellular pores for biomimetic applications

Abstract: Systematic approach to predicting selectivity of paracellular pores for biomimetic applications.

Cited by 8 publications

References 68 publications

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood–Brain Barrier Tight Junctions

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood–Brain Barrier Tight Junctions

Paracellular Gatekeeping: What Does It Take for an Ion to Pass Through a Tight Junction Pore?

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood-Brain-Barrier Tight-Junctions

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