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Atomistic molecular-dynamics simulations enable prediction of the Arginine Permeation Pathway through OccD1/OprD from pseudomonas aeruginosa

Atomistic molecular-dynamics simulations enable prediction of the Arginine Permeation Pathway through OccD1/OprD from pseudomonas aeruginosa
Atomistic molecular-dynamics simulations enable prediction of the Arginine Permeation Pathway through OccD1/OprD from pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-negative bacterium that does not contain large, nonspecific porins in its outer membrane. Consequently, the outer membrane is highly impermeable to polar solutes and serves as a barrier against the penetration of antimicrobial agents. This is one of the reasons why such bacteria are intrinsically resistant to antibiotics. Polar molecules that permeate across the outer membrane do so through substrate-specific channels proteins. To design antibiotics that target substrate-channel proteins, it is essential to first identify the permeation pathways of their natural substrates. In P. aeruginosa, the largest family of substrate-specific proteins is the OccD (previously reported under the name OprD) family. Here, we employ equilibrium and steered molecular-dynamics simulations to study OccD1/OprD, the archetypical member of the OccD family. We study the permeation of arginine, one of the natural substrates of OccD1, through the protein. The combination of simulation methods allows us to predict the pathway taken by the amino acid, which is enabled by conformational rearrangements of the extracellular loops of the protein. Furthermore, we show that arginine adopts a specific orientation to form the molecular interactions that facilitate its passage through part of the protein. We predict a three-stage permeation process for arginine.
0006-3495
1853-1861
Parkin, Jamie
5ddf8295-1355-4c4f-b8c2-cd1a828374dd
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Parkin, Jamie
5ddf8295-1355-4c4f-b8c2-cd1a828374dd
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394

Parkin, Jamie and Khalid, Syma (2014) Atomistic molecular-dynamics simulations enable prediction of the Arginine Permeation Pathway through OccD1/OprD from pseudomonas aeruginosa. Biophysical Journal, 107 (8), 1853-1861. (doi:10.1016/j.bpj.2014.08.035). (PMID:25418166)

Record type: Article

Abstract

Pseudomonas aeruginosa is a Gram-negative bacterium that does not contain large, nonspecific porins in its outer membrane. Consequently, the outer membrane is highly impermeable to polar solutes and serves as a barrier against the penetration of antimicrobial agents. This is one of the reasons why such bacteria are intrinsically resistant to antibiotics. Polar molecules that permeate across the outer membrane do so through substrate-specific channels proteins. To design antibiotics that target substrate-channel proteins, it is essential to first identify the permeation pathways of their natural substrates. In P. aeruginosa, the largest family of substrate-specific proteins is the OccD (previously reported under the name OprD) family. Here, we employ equilibrium and steered molecular-dynamics simulations to study OccD1/OprD, the archetypical member of the OccD family. We study the permeation of arginine, one of the natural substrates of OccD1, through the protein. The combination of simulation methods allows us to predict the pathway taken by the amino acid, which is enabled by conformational rearrangements of the extracellular loops of the protein. Furthermore, we show that arginine adopts a specific orientation to form the molecular interactions that facilitate its passage through part of the protein. We predict a three-stage permeation process for arginine.

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More information

Accepted/In Press date: 29 August 2014
Published date: 21 October 2014
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 374222
URI: http://eprints.soton.ac.uk/id/eprint/374222
ISSN: 0006-3495
PURE UUID: acf96c12-ba5d-4746-b3a6-f3e62fa97ca8
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 03 Mar 2015 13:38
Last modified: 20 Jul 2019 00:51

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Contributors

Author: Jamie Parkin
Author: Syma Khalid ORCID iD

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