Coarse-grained molecular dynamics simulations of membrane proteins and peptides

Bond, Peter J.; Holyoake, John; Ivetac, Anthony; Khalid, Syma; Sansom, Mark S. P.

doi:10.1016/j.jsb.2006.10.004

Cited by 299 publications

(322 citation statements)

References 114 publications

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“…With respect to the C154G mutant, both the DEER and single molecule FRET studies (5) show that, although ligand binding results in narrowing of the inward-facing cavity, no movement is observed on the periplasmic side. Several attempts to model structural changes in LacY by using molecular dynamics approaches have been undertaken recently (46)(47)(48)(49). DEER measurements of the type presented here should provide a powerful tool for guiding and evaluating these models.…”

Section: Discussionmentioning

confidence: 99%

Sugar binding induces an outward facing conformation of LacY

Смирнова

Kasho

Choe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

156

234

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According to x-ray structure, the lactose permease (LacY) is a monomer organized into N-and C-terminal six-helix bundles that form a deep internal cavity open on the cytoplasmic side with a single sugar-binding site at the apex. The periplasmic side of the molecule is closed. During sugar/H ؉ symport, a cavity facing the periplasmic side is thought to open with closure of the inwardfacing cytoplasmic cavity so that the sugar-binding site is alternately accessible to either face of the membrane. Double electronelectron resonance (DEER) is used here to measure interhelical distance changes induced by sugar binding to LacY. Nitroxidelabeled paired-Cys replacements were constructed at the ends of transmembrane helices on the cytoplasmic or periplasmic sides of wild-type LacY and in the conformationally restricted mutant Cys-1543 Gly. Distances were then determined in the presence of galactosidic or nongalactosidic sugars. Strikingly, specific binding causes conformational rearrangement on both sides of the molecule. On the cytoplasmic side, each of six nitroxide-labeled pairs exhibits decreased interspin distances ranging from 4 to 21 Å. Conversely, on the periplasmic side, each of three spin-labeled pairs shows increased distances ranging from 4 to 14 Å. Thus, the inward-facing cytoplasmic cavity closes, and a cleft opens on the tightly packed periplasmic side. In the Cys-1543 Gly mutant, sugarinduced closing is observed on the cytoplasmic face, but little or no change occurs on periplasmic side. The DEER measurements in conjunction with molecular modeling based on the x-ray structure provide strong support for the alternative access model and reveal a structure for the outward-facing conformer of LacY.conformational change ͉ double electron-electron resonance ͉ lactose permease ͉ major facilitator superfamily ͉ membrane transport T he lactose permease of Escherichia coli (LacY), a member of the major facilitator superfamily (MFS), utilizes free energy stored in an electrochemical H ϩ gradient (⌬˜Hϩ) to drive active transport by coupling the downhill, stoichiometric translocation of H ϩ with ⌬˜Hϩ to the uphill accumulation of galactopyranosides. In the absence of ⌬˜Hϩ, LacY can also use free energy released from downhill translocation of galactosides in either direction to drive uphill translocation of H ϩ with generation of ⌬˜Hϩ, the polarity of which depends on the direction of the sugar gradient (1, 2). An x-ray structure of LacY (3) combined with a wealth of biochemical data (1, 2, 4, 5) has led to an alternating access model for sugar translocation across the membrane. By this means, the inward-facing cytoplasmic cavity closes with opening of an outward-facing cleft, thereby making the sugar-binding site alternatively accessible to either face of the membrane. A similar model has been proposed for the glycerol phosphate/phosphate antiporter GlpT, a related MFS protein (6). The alternating access model involves a global conformational change, which is consistent with the highly dynamic nature of LacY (2, 7-9).A...

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Section: Discussionmentioning

confidence: 99%

Sugar binding induces an outward facing conformation of LacY

Смирнова

Kasho

Choe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

156

234

View full text Add to dashboard Cite

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“…27,28 Coarse-grained (CG) simulations, in which sets of atoms are grouped together to one bead, allow faster computation and have been used to probe biologically relevant time and length scales. 16,23,29,30 These models were shown to be successful in predicting bulk material properties 31 as well as in describing molecular level phenomena. [32][33][34] In this paper we explore the effect of hydrophobic mismatch on the cross-angle distribution of simulated TM helices.…”

Section: Introductionmentioning

confidence: 99%

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Benjamini

Smit

2013

Soft Matter

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Interactions of transmembrane (TM) helices play a key role in many cell processes. The configuration and cross angle these helices adopt are traditionally attributed to specific residue interactions. We present a different approach, in which specific residues are disregarded, and the role of the membrane in TM helix packing is investigated. We introduce a coarse-grained model of TM helices and obtain their characteristic configurations in the membrane both as a single helix and as paired helices. Our analysis shows that hydrophobic mismatch has a substantial effect in determining not only the tilt angles of TM helices but also the cross angles between helix pairs, for a large range of hydrophobic mismatches. We discuss the origin of this effect as well as the deviations from the common trend. Additionally, we explore the effect of hydrophobic mismatch on the Potential of Mean Force (PMF) between TM helices and discuss the importance of helical geometry in forming crossed configurations. Our observations suggest that hydrophobic mismatch must be taken into account when analyzing configurations of TM helix pairs. Hydrophobic mismatch through its effect on helix tilt can explain many cross-angle distribution features, making the role of specific interactions in determining helix pair configurations less significant.

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“…Here, we have used a CG force field that bridges the atomistic and CG levels of granularity described above to perform simulations of large systems. The force field was developed to explore lipid and detergent dynamics and has more recently been used to study protein-lipid systems (Bond & Sansom 2006;Bond et al 2007;Scott et al 2008) We have performed self-assembly simulations of a DNA dodecamer in DPPC and mixed DPPC/DMTAP lipid bilayers. Gene delivery via DNA-CL complexes relies not only upon the formation of the complex but also upon its dissociation to release the DNA once inside the cell, so that the DNA can migrate towards the cell nucleus.…”

Section: Introductionmentioning

confidence: 99%

DNA and lipid bilayers: self-assembly and insertion

Khalid

Bond

Holyoake

et al. 2008

J. R. Soc. Interface.

Self Cite

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DNA-lipid complexes are of biomedical importance as delivery vectors for gene therapy. To gain insight into the interactions of DNA with zwitterionic and cationic (dimyristoyltrimethylammonium propane (DMTAP)) lipids, we have used coarse-grained molecular dynamics simulations to study the self-assembly of DPPC and DPPC/DMTAP lipid bilayers in the presence of a DNA dodecamer. We observed the spontaneous formation of lipid bilayers from initial systems containing randomly placed lipids, water-counterions and DNA. In both the DPPC and DPPC/DMTAP simulations, the DNA molecule is located at the water-lipid headgroup interface, lying approximately parallel to the plane of the bilayer. We have also calculated the potential of mean force for transferring a DNA dodecamer through a DPPC/DMTAP bilayer. A high energetic barrier to DNA insertion into the hydrophobic core of the bilayer is observed. The DNA adopts a transmembrane orientation only in this region. Local bilayer deformation in the vicinity of the DNA molecule is observed, largely as a result of the DNA-DMTAP headgroup attraction.

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Coarse-grained molecular dynamics simulations of membrane proteins and peptides

Cited by 299 publications

References 114 publications

Sugar binding induces an outward facing conformation of LacY

Sugar binding induces an outward facing conformation of LacY

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

DNA and lipid bilayers: self-assembly and insertion

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