Principles of membrane protein structure

Sansom, Mark S. P.; Kerr, Ian D.

doi:10.1016/s1874-5342(06)80054-1

Cited by 5 publications

(2 citation statements)

References 141 publications

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“…An interfacial location for aromatic side chains has been observed in a number of membrane proteins for which structures have been determined. (46) Vpu from HIV-1 Vpu is an integral membrane protein encoded by HIV-1. (47) It is 80-82 residues long, containing a single TM helix from residues 6-28.…”

Section: Nb From Influenza Bmentioning

confidence: 99%

Viral ion channels: molecular modeling and simulation

1999

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In a number of membrane-bound viruses, ion channels are formed by integral membrane proteins. These channel proteins include M2 from influenza A, NB from influenza B, and, possibly, Vpu from HIV-1. M2 is important in facilitating uncoating of the influenza A viral genome and is the target of amantadine, an anti-influenza drug. The biological roles of NB and Vpu are less certain. In all cases, the protein contains a single transmembrane ␣-helix close to its N-terminus. Channels can be formed by homo-oligomerization of these proteins, yielding bundles of transmembrane helices that span the membrane and surround a central ion-permeable pore. Molecular modeling may be used to integrate and interpret available experimental data concerning the structure of such transmembrane pores. This has proved successful for the M2 channel domain, where two independently derived models are in agreement with one another, and with solid-state nuclear magnetic resonance (NMR) data. Simulations based on channel models may yield insights into possible ion conduction and selectivity mechanisms.

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Section: Nb From Influenza Bmentioning

confidence: 99%

Viral ion channels: molecular modeling and simulation

1999

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“…The majority of integral membrane proteins appear to be made up of bundles of transmembrane (TM) ␣-helices (Sansom and Kerr, 1995). A number of different algorithms have been developed (Cserzo et al, 1994;Jones et al, 1994;Persson and Argos, 1994;Rost et al, 1996;von Heijne, 1992) that predict the number and location of such TM helices within the sequence of a membrane protein with a high degree of accuracy.…”

Section: Introductionmentioning

confidence: 99%

Defining the Transmembrane Helix of M2 Protein from Influenza A by Molecular Dynamics Simulations in a Lipid Bilayer

Forrest

Tieleman

Sansom

1999

Biophysical Journal

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Integral membrane proteins containing at least one transmembrane (TM) alpha-helix are believed to account for between 20% and 30% of most genomes. There are several algorithms that accurately predict the number and position of TM helices within a membrane protein sequence. However, these methods tend to disagree over the beginning and end residues of TM helices, posing problems for subsequent modeling and simulation studies. Molecular dynamics (MD) simulations in an explicit lipid and water environment are used to help define the TM helix of the M2 protein from influenza A virus. Based on a comparison of the results of five different secondary structure prediction algorithms, three different helix lengths (an 18mer, a 26mer, and a 34mer) were simulated. Each simulation system contained 127 POPC molecules plus approximately 3500-4700 waters, giving a total of approximately 18,000-21,000 atoms. Two simulations, each of 2 ns duration, were run for the 18mer and 26mer, and five separate simulations were run for the 34mer, using different starting models generated by restrained in vacuo MD simulations. The total simulation time amounted to 11 ns. Analysis of the time-dependent secondary structure of the TM segments was used to define the regions that adopted a stable alpha-helical conformation throughout the simulation. This analysis indicates a core TM region of approximately 20 residues (from residue 22 to residue 43) that remained in an alpha-helical conformation. Analysis of atomic density profiles suggested that the 18mer helix revealed a local perturbation of the lipid bilayer. Polar side chains on either side of this region form relatively long-lived H-bonds to lipid headgroups and water molecules.

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Stoichiometry of lipid-protein interaction and integral membrane protein structure

Marsh¹

1997

European Biophysics Journal

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The stoichiometry of the first shell of lipids interacting with a transmembrane protein is defined operationally by the population of spin-labeled lipid chains whose motion is restricted directly by the protein. Interaction stoichiometries have been determined experimentally for a wide range of a-helical integral membrane proteins by using spin-label ESR spectroscopy. Here, we determine the spatially defined number of first-shell lipids at the hydrophobic perimeter of integral membrane proteins whose 3D structure has been determined by X-ray crystallography and lipid-protein interactions characterized by spin-labeling. Molecular modeling is used to build a single shell of lipids surrounding transmembrane structures derived from the PDB. Constrained energy optimization of the protein-lipid assemblies is performed by molecular mechanics. For relatively small proteins (up to 7-12 transmembrane helices), the geometrical first shell corresponds to that defined experimentally by perturbation of the lipid-chain dynamics. For larger, multi-subunit a-helical proteins, the lipids perturbed directly by the protein may either exceed or be less in number than those that can be accommodated at the intramembranous perimeter. In these latter cases, the motionally restricted spinlabeled lipids can be augmented by intercalation, or can correspond to a specific subpopulation at the protein interface, respectively. For monomeric b-barrel proteins, the geometrical lipid stoichiometry corresponds to that determined from lipid mobility for a 22-stranded barrel, but fewer lipids are motionally restricted than can be accommodated around an eight-stranded barrel. Deviations from the geometrical first shell, in the b-barrel case, are for the smaller protein with a highly curved barrel.

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Principles of membrane protein structure

Cited by 5 publications

References 141 publications

Viral ion channels: molecular modeling and simulation

Viral ion channels: molecular modeling and simulation

Defining the Transmembrane Helix of M2 Protein from Influenza A by Molecular Dynamics Simulations in a Lipid Bilayer

Stoichiometry of lipid-protein interaction and integral membrane protein structure

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