Simulations of substrate transport in the multidrug transporter EmrD

Joseph Baker, Stephen Wright, Florence Tama

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta-chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters.

Original languageEnglish (US)
Pages (from-to)1620-1632
Number of pages13
JournalProteins: Structure, Function and Genetics
Volume80
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Multiple Drug Resistance
Molecular Dynamics Simulation
Molecular dynamics
Substrates
Periplasm
Computer simulation
Protein Transport
Escherichia coli
Phospholipids
Cytoplasm
Proteins
Cell Membrane
Membranes
phenylhydrazone

Keywords

  • Major facilitator superfamily
  • Membrane transporter
  • Steered molecular dynamics

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

Simulations of substrate transport in the multidrug transporter EmrD. / Baker, Joseph; Wright, Stephen; Tama, Florence.

In: Proteins: Structure, Function and Genetics, Vol. 80, No. 6, 06.2012, p. 1620-1632.

Research output: Contribution to journalArticle

@article{f12d977efe524f31ba194a2f51b25f9d,
title = "Simulations of substrate transport in the multidrug transporter EmrD",
abstract = "EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta-chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters.",
keywords = "Major facilitator superfamily, Membrane transporter, Steered molecular dynamics",
author = "Joseph Baker and Stephen Wright and Florence Tama",
year = "2012",
month = "6",
doi = "10.1002/prot.24056",
language = "English (US)",
volume = "80",
pages = "1620--1632",
journal = "Proteins: Structure, Function and Genetics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Simulations of substrate transport in the multidrug transporter EmrD

AU - Baker, Joseph

AU - Wright, Stephen

AU - Tama, Florence

PY - 2012/6

Y1 - 2012/6

N2 - EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta-chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters.

AB - EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta-chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters.

KW - Major facilitator superfamily

KW - Membrane transporter

KW - Steered molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=84860631049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860631049&partnerID=8YFLogxK

U2 - 10.1002/prot.24056

DO - 10.1002/prot.24056

M3 - Article

C2 - 22434745

AN - SCOPUS:84860631049

VL - 80

SP - 1620

EP - 1632

JO - Proteins: Structure, Function and Genetics

JF - Proteins: Structure, Function and Genetics

SN - 0887-3585

IS - 6

ER -