Molecular Dynamics Simulations of Ion Selectivity
in a Claudin-15 Paracellular Channel
Version 2 2018-11-16, 18:05
Version 1 2018-11-15, 22:21
Posted on 2018-11-16 - 18:05
Claudins are tissue-specific
transmembrane proteins able to form
junctions between two cells and regulate the flow of physiological
solutes parallel to the cell walls, that is, the paracellular transport.
Claudin-15 is highly expressed in the intestine where it forms efficient
Na+ channels and Cl– barriers. However,
the molecular details of these biological complexes are still unclear.
Here, the permeation process of Na+, K+, and
Cl– ions inside a refined structural model of a
claudin-15 paracellular channel is investigated using all-atom molecular
dynamics simulations in a double-bilayer and explicit solvent. One-dimensional
potential of mean force (PMF) profiles, calculated using umbrella
sampling (US) simulations, show that the channel allows the passage
of the two physiological cations while excluding chloride. These features
are generated by the action of several acidic residues, in particular
the ring of D55 residues which is located at the narrowest region
of the pore, in correspondence with the energy minimum for cations
and the peak for chloride. We also used the Voronoi-tessellated milestoning
method to obtain additional PMF profiles and the permeation timescale
of the three ions. The milestoning PMFs agree well with those obtained
by US, and the rate calculation reveals that the passage of chloride
is almost 30 times slower than that of sodium. Our results are consistent
with the known ability of claudin-15 to regulate tight junction selectivity
and with the experimentally determined role of the acidic residues.
This further validates our structural model and provides insights
into the atomistic details of ion transport in paracellular channels
that could be shared by other claudin-based architectures.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Alberini, Giulio; Benfenati, Fabio; Maragliano, Luca (2018). Molecular Dynamics Simulations of Ion Selectivity
in a Claudin-15 Paracellular Channel. ACS Publications. Collection. https://doi.org/10.1021/acs.jpcb.8b06484
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (3)
GA
Giulio Alberini
FB
Fabio Benfenati
LM
Luca Maragliano