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Movement of arginine through OprD: The energetics of permeation and the role of lipopolysaccharide in directing arginine to the protein

Movement of arginine through OprD: The energetics of permeation and the role of lipopolysaccharide in directing arginine to the protein
Movement of arginine through OprD: The energetics of permeation and the role of lipopolysaccharide in directing arginine to the protein
The outer membrane channel OprD from Pseudomonas aeruginosa transports basic amino acids and clinically relevant carbapenem antibiotics. Understanding the molecular basis of substrate permeation across this channel will therefore lead to better therapeutic designs to treat infections. Using umbrella sampling simulations, we calculated the potential of mean force (PMF) for the arginine permeation pathway through OprD. The PMF reveals a deep free energy well of ~6 kT around the putative substrate binding site followed by a shallower well of ~4 kT close to the most constricted region of the pore. Despite becoming partially dehydrated during translocation, some water molecules are retained to shield the guanidinium side chain of arginine from the ladder of basic residues in the protein. Sugars of the lipopolysaccharide headgroups form contacts with arginine and could potentially play an important role in transferring substrate from the external medium to OprD. The PMF through bulk membrane shows a large energetic barrier of ~45 kT within the hydrophobic core of the membrane, suggesting that spontaneous translocation without OprD is highly unlikely. This significant energetic penalty is likely caused by the extensive distortion of the lower leaflet of the outer membrane as phospholipid headgroups sink inwards to interact with charged groups of arginine. Our results provide quantitative insights into solute permeation across bacterial outer membrane.
1520-5207
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394

Samsudin, Firdaus and Khalid, Syma (2019) Movement of arginine through OprD: The energetics of permeation and the role of lipopolysaccharide in directing arginine to the protein. The Journal of Physical Chemistry B. (doi:10.1021/acs.jpcb.9b00063).

Record type: Article

Abstract

The outer membrane channel OprD from Pseudomonas aeruginosa transports basic amino acids and clinically relevant carbapenem antibiotics. Understanding the molecular basis of substrate permeation across this channel will therefore lead to better therapeutic designs to treat infections. Using umbrella sampling simulations, we calculated the potential of mean force (PMF) for the arginine permeation pathway through OprD. The PMF reveals a deep free energy well of ~6 kT around the putative substrate binding site followed by a shallower well of ~4 kT close to the most constricted region of the pore. Despite becoming partially dehydrated during translocation, some water molecules are retained to shield the guanidinium side chain of arginine from the ladder of basic residues in the protein. Sugars of the lipopolysaccharide headgroups form contacts with arginine and could potentially play an important role in transferring substrate from the external medium to OprD. The PMF through bulk membrane shows a large energetic barrier of ~45 kT within the hydrophobic core of the membrane, suggesting that spontaneous translocation without OprD is highly unlikely. This significant energetic penalty is likely caused by the extensive distortion of the lower leaflet of the outer membrane as phospholipid headgroups sink inwards to interact with charged groups of arginine. Our results provide quantitative insights into solute permeation across bacterial outer membrane.

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More information

Accepted/In Press date: 6 March 2019
e-pub ahead of print date: 6 March 2019

Identifiers

Local EPrints ID: 429252
URI: http://eprints.soton.ac.uk/id/eprint/429252
ISSN: 1520-5207
PURE UUID: 27530667-6587-4de3-ac25-026ea1d0a12c
ORCID for Firdaus Samsudin: ORCID iD orcid.org/0000-0003-2766-4459
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 25 Mar 2019 17:30
Last modified: 06 Mar 2020 05:01

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