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@INPROCEEDINGS{Bondar:1025183,
author = {Bondar, Ana-Nicoleta and Hristova, Kalina and Wimley,
William C.},
title = {{M}echanism by which water interactions stabilize a
p{H}-dependent membrane pore},
issn = {0006-3495},
reportid = {FZJ-2024-02760},
year = {2024},
abstract = {Peptides that can form large, stable pores at acidic pH
values are of direct interest to deliver cargo to cells and
cell compartments with acidic pH. Peptides of the pHD
(pH-dependent delivery peptides) have the unique property of
forming stable pores with diameters of ∼30–-100 Å at pH
below ∼6. Such a pore size could be established with
∼8–30 peptides, and each peptide carries several
sidechains that can titrate at the pH of interest.
Understanding which protonation states are compatible with
stable pore formation is essential, as it could guide
rational design of new peptides with pore-forming properties
tailored to specific cells and cell compartments. We report
on experiment-guided atomistic simulations that probe the
protonation-coupled structure and dynamics of pHD pores. To
identify interactions that could contribute to the stability
of the pores, we used the Bridge/Bridge2 graph algorithm and
graphical user interface to compute the hydrogen-bond
networks sampled by the peptides, lipid phosphate groups,
and water. We identify a complex network of interactions
between peptides, lipid headgroups, and water molecules,
with water molecules bridging neighboring peptides via
dynamic hydrogen bonding. Research was supported in part by
the National Institutes of Health award no. 1R01GM151326-01
and by the computing time allocation PHDPORES from the
JURECA-DC Supercomputing Cluster of the Forschungszentrum
Jülich.},
month = {Feb},
date = {2024-02-10},
organization = {Biophysical Society Meeting,
Philadelphia (USA), 10 Feb 2024 - 14
Feb 2024},
cin = {IAS-5 / INM-9},
ddc = {570},
cid = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)1},
doi = {10.1016/j.bpj.2023.11.2011},
url = {https://juser.fz-juelich.de/record/1025183},
}