TCB Publications

Light harvesting complex II B850 excitation dynamics.

Johan Strumpfer and Klaus Schulten. Light harvesting complex II B850 excitation dynamics. Journal of Chemical Physics, 2010. In press.

The dynamics of excitation energy transfer within the B850 ring of light harvesting complex 2 from Rhodobacter sphaeroides and between neighboring B850 rings is investigated by means of dissipative quantum mechanics. The assumption of Boltzmann populated donor states for the calculation of inter-complex excitation transfer rates by generalized Förster theory is shown to give accurate results as intra-complex exciton relaxation occurs in a few ps. The primary channels of exciton transfer between B850 rings are found to be the five lowest-lying exciton states, with the non-850 nm states making significant contributions to the total transfer rate.

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Tertiary and secondary structure elasticity of a six-Ig titin chain.

Eric H. Lee, Jen Hsin, Eleonore von Castelmur, Olga Mayans, and Klaus Schulten. Tertiary and secondary structure elasticity of a six-Ig titin chain. Biophysical Journal, 2010. In press.

The protein titin functions as a mechanical spring conferring passive elasticity to muscle. Force spectroscopy studies have shown that titin exhibits several regimes of elasticity. Dis-ordered segments bring about a soft, entropic spring-type elasticity; secondary structures of titin�s immunoglobulin-like (Ig-) and fibronectin type III-like (FN-III) domains provide a stiff elasticity. In this study we demonstrate a third type of elasticity due to tertiary structure and involving domain-domain interaction and reorganization along the titin chain. Through altogether 870 ns of molecular dynamics (MD) simulations involving 29,000 � 635,000 atom systems, the mechanical properties of a six-Ig domain of titin (I65-I70), for which a crys- tallographic structure is available, are probed. The results reveal a soft tertiary structure elasticity. A remarkably accurate statistical mechanical description for this elasticity is derived and applied. Simulations studied also the stiff, secondary structure elasticity of the I65-I70 chain due to the unraveling of its domains and revealed how force propagates along the chain during the secondary structure elasticity response.

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Structural insight into nascent polypeptide chain-mediated translational stalling.

Birgit Seidelt, C. Axel Innis, Daniel N. Wilson, Marco Gartmann, Jean-Paul Armache, Elizabeth Villa, Leonardo G. Trabuco, Thomas Becker, Thorsten Mielke, Klaus Schulten, Thomas A. Steitz, and Roland Beckmann. Structural insight into nascent polypeptide chain-mediated translational stalling. Science, 2009. Published online October 29 2009; 10.1126/science.1177662.

Expression of the Escherichia coli tryptophanase operon under inducing tryptophan concentrations is dependent upon ribosome stalling during translation of the upstream TnaC leader peptide. Interaction between the TnaC nascent chain and the ribosomal tunnel is thought to be critical for efficient stalling. We have determined a 5.8 resolution cryo-EM and single particle reconstruction of an E. coli 70S ribosome stalled during translation of the TnaC leader gene. The quality of the map allows the ordered TnaC nascent chain to be observed within the exit tunnel of the ribosome, making contacts with ribosomal components at distinct sites. At the peptidyltransferase center of the ribosome, the universally conserved A2602 and U2585 adopt conformations that are incompatible with co-habitation of the termination release factors. The TnaC interactions within the tunnel are suggested to produce structural changes that are relayed to inactivate the peptidyltransferase center. This study clearly indicates that individual nascent chains can adopt distinct conformations within the exit tunnel.

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Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome.

Thomas Becker, Elisabet Mandon, Shashi Bhushan, Alexander Jarasch, Jean-Paul Armache, Soledad Funes, Fabrice Jossinet, James Gumbart, Thorsten Mielke, Otto Berninghausen, Klaus Schulten, Eric Westhof, Reid Gilmore, and Roland Beckmann. Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome. Science, 2009. Published online October 29 2009; 10.1126/science.1178535.

The trimeric Sec61/SecY complex is serving a vital function as a protein-conducting channel (PCC) for secretory and membrane proteins. Although Sec complexes can form oligomers, the crystal structures of prokaryotic SecY complexes and other data suggest that a single copy may serve as an active PCC. Here, we present sub-nanometer resolution cryo-EM structures of eukaryotic ribosome-Sec61 complexes in combination with biochemical data demonstrating that in both states, idle and active, the Sec complex is non-oligomeric and interacts mainly via loop 8 with the universal ribosomal adaptor site. In the active state the ribosomal tunnel and a central pore of the monomeric PCC are occupied by the nascent chain contacting loop 6 of the Sec complex. Our findings provide the structural basis for understanding the activity of a solitary Sec complex in cotranslational translocation.

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A glycophorin A-like framework for the dimerization of photosynthetic core complexes.

Jen Hsin, Chris Chipot, and Klaus Schulten. A glycophorin A-like framework for the dimerization of photosynthetic core complexes. Journal of the American Chemical Society, 2009. Article ASAP.

The core complex in photosynthetic bacteria plays a central role in photosynthesis. This molecular assembly is composed of two protein complexes, viz., the light-harvesting complex I (LH1), which absorbs sunlight by means of the protein-bound bacteriochlorophylls, and the reaction center (RC), which uses the light-excitation energy absorbed by the LH complexes to produce a transmembrane (TM) charge gradient, subsequently employed for energy conversion. In Rhodobacter (Rba.) sphaeroides, the core complex contains, in addition, two copies of the single TM -helix protein, PufX, and forms a (RC-LH1-PufX) dimer. To this date, no high-resolution structure has been reported for the entire core complex. In particular, the location of PufX within the (RC-LH1-PufX) dimer is still the subject of much debate. Here, one of the proposed locations for PufX, requiring its dimerization, is examined. The PufX-dimer model on the basis of the glycophorin A (GpA) dimer was constructed, and its robustness was probed through a series of molecular dynamics (MD) simulations. The free-energy change due to the replacement of Gly35 by valine was also determined to assess whether this mutation is responsible for distinct PufX oligomerization states in different Rba. species. The present study shows that PufX helices form a stable GpA-like dimer with a helix-helix crossing angle that could constitute the molecular basis of the reported highly bent and V-shaped structure of the Rba. sphaeroides core complex dimer.

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Multi-scale simulations of membrane sculpting by N-BAR domains.

Ying Yin, Anton Arkhipov, and Klaus Schulten. Multi-scale simulations of membrane sculpting by N-BAR domains. In Philip Biggin and Mark Sansom, editors, Molecular Simulations and Biomembranes: From Biophysics to Function. Royal Society of Chemistry, 2010.

Cells contain membranes of various shapes, often formed with the help of cellular proteins. In particular, proteins of the BAR domain superfamily participate in various membrane sculpting processes, bending membranes through the concerted action of multiple BAR domains arranged in lattices. Despite extensive experimental studies, information on the dynamics of membrane bending and an explanation of the lattices� role are still lacking. Computational studies can furnish such information. Here we summarize recent work on the dynamics of membrane bending by N-BAR domains, a well-studied member of the BAR domain superfamily, at four levels of resolution: described by all-atom molecular dynamics, residue-based coarse graining (resolving single amino acids and lipid molecules), shape-based coarse graining (resolving overall protein and membrane shapes), and a continuum elastic membrane model. Simulations showed how the membrane curvature generated depends on the arrangement of N-BAR domains on the membrane surface. The lattice arrangements found to be optimal for producing high membrane curvature are composed of protein rows separated by 5 nm, stability of the rows being maintained through electrostatic interactions between N-BAR domains. Formation of entire membrane tubes by lattices of N-BAR domains over time scales of 200 s was observed in coarse-grained simulations; an all-atom simulation of a 2.3 million atom system covering 0.3s complemented the coarse-grained simulations.

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Regulation of the protein-conducting channel by a bound ribosome.

James Gumbart, Leonardo G. Trabuco, Eduard Schreiner, Elizabeth Villa, and Klaus Schulten. Regulation of the protein-conducting channel by a bound ribosome. Structure, 17:1453-1464, 2009.

During protein synthesis, it is often necessary for the ribosome to form a complex with a membrane-bound channel, the SecY/Sec61 complex, in order to translocate nascent proteins across a cellular membrane. Structural data on the ribosome-channel complex are currently limited to low-resolution cryo-electron microscopy maps, including most recently one showing a bacterial ribosome bound to a monomeric SecY complex. Using that map along with molecular dynamics flexible fitting, we have modeled and simulated an atomic-resolution structure of the ribosome-channel complex. We characterized the sites of interaction within the complex and determined the effects of ribosome binding on the SecY channel. We also constructed a model of a ribosome in complex with a SecY dimer, finding that in simulation the dimer enhances ribosome binding and destabilizes a channel-blocking plug, preparing the channel to receive the nascent polypeptide. The study involved 2.7-million-atom simulations over altogether nearly 50 ns.

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Polarizable intermolecular potentials for water and benzene interacting with halide and metal ions.

Fabien Archambault, Christophe Chipot, Ignacio Soteras, F. Javier Luque, Klaus Schulten, and Francois Dehez. Polarizable intermolecular potentials for water and benzene interacting with halide and metal ions. Journal of Chemical Theory and Computation, 5:3022-3031, 2009.

A complete derivation of polarizable intermolecular potentials based on high-level, gasphase quantum-mechanical calculations is proposed. The importance of appreciable accuracy together with inherent simplicity represents a significant endeavor when enhancement of existing force fields for biological systems is sought. Toward this end, symmetry-adapted perturbation theory (SAPT) can provide an expansion of the total interaction energy into physically meaningful e.g. electrostatic, induction and van der Waals terms. Each contribution can be readily compared with its counterpart in classical force fields. Since the complexity of the different intermolecular terms cannot be fully embraced using a minimalist description, it is necessary to resort to polyvalent expressions capable of encapsulating overlooked contributions from the quantum-mechanical expansion. This choice results in consistent force field components that reflect the underlying physical principles of the phenomena. This simplified potential energy function is detailed and definitive guidelines are drawn. As a proof of concept, the methodology is illustrated through a series of test cases that include the interaction of water and benzene with halide and metal ions. In each case considered, the total energy is reproduced accurately over a range of biologically relevant distances.

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Membrane curvature induced by aggregates of LH2s and monomeric LH1s.

Danielle E. Chandler, James Gumbart, John D. Stack, Christophe Chipot, and Klaus Schulten. Membrane curvature induced by aggregates of LH2s and monomeric LH1s. Biophysical Journal, 97, 2009. In press.

The photosynthetic apparatus of purple bacteria is contained within organelles called chromatophores, which form as extensions of the cytoplasmic membrane. The shape of these chromatophores can be spherical (as in Rb. sphaeroides), lamellar (as in Rps. acidophila and Rs. molischianum), or tubular (as in certain Rb. sphaeroides mutants). Chromatophore shape is thought to be induced and maintained by the integral membrane proteins Light Harvesting Complexes I and II (LH1 and LH2), which pack tightly together in the chromatophore. It has been suggested that the shape of LH2, together with its close packing in the membrane, induces membrane curvature, although it is not known why. The mechanism of LH2-induced curvature is explored via molecular dynamics simulations of multiple LH2 complexes in a membrane patch. LH2s from three species - Rb. sphaeroides, Rps. acidophila, and Rs. molischianum - were simulated in different packing arrangements. In each case, the LH2s pack together and tilt with respect to neighboring LH2s in a way that produces an overall curvature. This curvature appears to be caused by a combination of LH2 shape and electrostatic repulsion between cytoplasmic charged residues, the removal of which severely reduces LH2 curvature. The interaction between LH2s and LH1 monomers is also explored via molecular dynamics simulations; these simulations suggest that curvature is diminished by the presence of LH1 monomers. The implications of our results for chromatophore shape are discussed.

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Discovery through the computational microscope.

Eric H. Lee, Jen Hsin, Marcos Sotomayor, Gemma Comellas, and Klaus Schulten. Discovery through the computational microscope. Structure, 17:1295-1306, 2009.

All-atom molecular dynamics simulations have become increasingly popular as a tool to investigate protein function and dynamics. However, researchers are concerned about the short time scales covered by simulations, the apparent impossibility to model large and integral biomolecular systems, and the actual predictive power of the molecular dynamics methodology. Here we review simulations of proteins with mainly mechanical functions (titin, fibrinogen, ankyrin, and cadherin) that were in the past hotly disputed and also considered key successes. The simulation work covered shows how state-of-the-art modeling alleviates some of the prior concerns, and how unrefuted discoveries are made through the �computational microscope�.

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Membrane-bending mechanism of amphiphysin N-BAR domains.

Anton Arkhipov, Ying Yin, and Klaus Schulten. Membrane-bending mechanism of amphiphysin N-BAR domains. Biophysical Journal, 97:2727-2735, 2009.

BAR domains are highly conserved protein domains participating in a diversity of cellular processes that involve membrane remodeling. The mechanisms underlying such remodeling are debated. For the relatively well studied case of amphiphysin N-BAR domain, one suggested mechanism involves scaffolding, i.e., binding of a negatively charged membrane to the protein�s positively charged curved surface. An alternative mechanism suggests that insertion of the protein�s N-terminal amphipathic segments (N-helices H0) into the membrane leads to bending. Here, we address the issue through all-atom and coarse-grained simulations of multiple amphiphysin N-BAR domains and their segments interacting with a membrane. We observe that BAR domains without H0s bend the membrane, but H0s alone do not, which suggests that scaffolding, rather than helix insertion, plays a key role in membrane sculpting by amphiphysin N-BAR domains.

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Common structural transitions in explicit-solvent simulations of villin headpiece folding.

Peter L. Freddolino and Klaus Schulten. Common structural transitions in explicit-solvent simulations of villin headpiece folding. Biophysical Journal, 97:2338-2347, 2009.

Molecular dynamics simulations of protein folding can provide very high resolution data on the folding process; however, due to computational challenges most studies of protein folding have been limited to small peptides, or made use of approximations such as Go potentials or implicit solvent models. We have performed a set of molecular dynamics simulations totaling over 50 microseconds on the villin headpiece subdomain, one of the most stable and fastest-folding naturally occurring proteins, in explicit solvent. We find that the wild type villin headpiece reliably folds to a native conformation on timescales similar to experimentally observed folding, but that a fast folding double-norleucine mutant shows significantly more heterogeneous behavior. Along with other recent simulation studies, we note the occurrence of non-native structures which may yield a native-like signal in the fluorescence measurements typically used to study villin folding. Based on the wild type simulations we propose alternative approaches to measure the formation of the native state.

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Elucidating the mechanism behind irreversible deformation of viral capsids.

Anton Arkhipov, Wouter H. Roos, Gijs J. L. Wuite, and Klaus Schulten. Elucidating the mechanism behind irreversible deformation of viral capsids. Biophysical Journal, 97:2061-2069, 2009.

Atomic force microscopy (AFM) has recently provided highly precise measurements of mechanical properties of various viruses. However, molecular details underlying viral mechanics remain unresolved. Here we report AFM nanoindentation experiments on T=4 hepatitis B virus (HBV) capsids combined with coarse-grained molecular dynamics simulations, which permit interpretation of experimental results at the molecular level. The force response of the indented capsid recorded in simulations agrees with experimental observations. In both experiments and simulations, irreversible capsid deformation is observed for deep indentations. Simulations show the irreversibility to be due to local bending and shifting of capsid proteins, rather than their global rearrangement. These results emphasize the viability of large capsid deformations without significant changes of the mutual positions of HBV capsid proteins, in contrast to the stiffer capsids of other viruses, which exhibit more extensive contacts between their capsid proteins than in the case of HBV.

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Ligand migration and cavities within scapharca dimeric HbI: Studies by time-resolved crystallography, Xe binding and computational analysis.

James E. Knapp, Reinhard Pahl, Jordi Cohen, Jeffry C. Nichols, Klaus Schulten, Quentin H. Gibson, Vukica Srajer, and William E. Royer Jr. Ligand migration and cavities within scapharca dimeric HbI: Studies by time-resolved crystallography, Xe binding and computational analysis. Structure, 17:1494-1504, 2009.

As in many other hemoglobins, no direct route for migration of ligands between solvent and active site is evident from crystal structures of Scapharca inaequivalvis dimeric HbI. Xenon (Xe) and organic halide binding experiments along with computational analysis presented here reveal protein cavities as potential ligand migration routes. Time-resolved crystallographic experiments show that photodissociated carbon monoxide (CO) docks within 5ns at the distal pocket B-site and at more remote Xe4 and Xe2 cavities. CO rebinding is not affected by the presence of dichloroethane within the major Xe4 protein cavity, demonstrating that this cavity is not on the major exit/entrance pathway. The crystal lattice has a substantial influence on ligand migration, suggesting that significant conformational rearrangements may be required for ligand exit. Taken together, these results are consistent with a distal histidine gate as one important ligand entry and exit route, despite its participation in the dimeric interface.

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Molecular control of ionic conduction in polymer nanopores.

Eduardo R. Cruz-Chu, Thorsten Ritz, Zuzanna S. Siwy, and Klaus Schulten. Molecular control of ionic conduction in polymer nanopores. Faraday Discussion, 143:47-62, 2009.

Polymeric nanopores show unique transport properties and have attracted a great deal of scientific interest as a test system to study ionic and molecular transport at the nanoscale. By means of all-atom molecular dynamics (MD), we studied the ion dynamics inside polymeric polyethylene terephthalate (PET) nanopores. To carry out these MD simulations, we established a collapsing-annealing protocol to assemble periodic atomic models of polymeric materials and built a PET nanopore model that replicates the key features of experimental devices, namely the conical geometry and the negative surface charge density. Our MD simulations showed that the protonation state of the carboxyl group of exposed PET residues had a considerable effect on the ion selectivity, affecting the ionic densities and electrostatic potentials inside the nanopores. The effects of high concentrations of Ca ions within the pore are investigated in detail, so as gain insight into possible charge inversion effects, as have been reported in experiments.

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Maturation of high-density lipoproteins.

Amy Y. Shih, Stephen G. Sligar, and Klaus Schulten. Maturation of high-density lipoproteins. Journal of the Royal Society Interface, 6:863-871, 2009.

Human high-density lipoproteins (HDL) are involved in the transport of lipids and cholesterol through the blood stream protecting people from vascular diseases. The mechanism by which HDL functions is not well understood due to a lack of structural information, in particular of the mature circulating spherical HDL particles. Here we report an atomic level view of spherical HDL furnished through molecular dynamics simulations. An intermediate form, discoidal HDL, had been characterized through experimental observations and computational modeling involving coarse-grained and all-atom molecular dynamics. Discoidal HDL is typically composed of two belt-like apolipoprotein A-I strands encircling a lipid bilayer. We have extend the prior computational modeling to investigate the maturation of discoidal HDL to spherical HDL which contains numerous molecules of cholesterol ester. Sixty cholesterol ester molecules were added in a stepwise fashion in order to mimic how HDL particles naturally mature. The resulting matured particle, captured first in a coarse-grained description, was then described in a consistent all-atom representation and analyzed in chemical detail. The simulations show that HDL maturation results from the formation of a hydrophobic core comprised of cholesterol ester molecules surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation with flexible N- and C-terminal helices and a stable central region (helices 3 to 7) stabilized by salt-bridges. The central region binds with and activates the enzyme lectithin cholesterol acyl transferase that converts cholesterol into cholesterol ester for incorporation into HDL.

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Protein-induced membrane curvature investigated through molecular dynamics flexible fitting.

Jen Hsin, James Gumbart, Leonardo G. Trabuco, Elizabeth Villa, Pu Qian, C. Neil Hunter, and Klaus Schulten. Protein-induced membrane curvature investigated through molecular dynamics flexible fitting. Biophysical Journal, 97:321-329, 2009.

In the photosynthetic purple bacterium Rhodobacter () sphaeroides, light is absorbed by membrane-bound light-harvesting (LH) proteins LH1 and LH2. LH1 directly surrounds the reaction center (RC) and, together with PufX, forms a dimeric (RC-LH1-PufX) protein complex. In LH2-deficient Rba. sphaeroides mutants, RC-LH1-PufX dimers aggregate into tubular vesicles with a radius of 250-550 Å, making RC-LH1-PufX one of the few integral membrane proteins known to actively induce membrane curvature. Recently, a three-dimensional electron microscopy density map showed that the Rba. sphaeroides RC-LH1-PufX dimer exhibits a prominent bend at its dimerizing interface. To investigate the curvature properties of this highly bent protein, we employed molecular dynamics simulations to fit an all-atom structural model of the RC-LH1-PufX dimer within the electron microscopy density map. The simulations reveal how the dimer produces a membrane with high local curvature, even though the location of PufX cannot yet be determined uniquely. The resulting membrane curvature agrees well with the size of RC-LH1-PufX tubular vesicles, and demonstrates how the local curvature properties of the RC-LH1-PufX dimer propagate to form the observed long-range organization of the Rba. sphaeroides tubular vesicles.

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Molecular Dynamics Flexible Fitting: A practical guide to combine cryo-electron microscopy and X-ray crystallography.

Leonardo G. Trabuco, Elizabeth Villa, Eduard Schreiner, Christopher B. Harrison, and Klaus Schulten. Molecular Dynamics Flexible Fitting: A practical guide to combine cryo-electron microscopy and X-ray crystallography. Methods, 49:174-180, 2009.

Hybrid computational methods for combining structural data from different sources and resolutions are becoming an essential part of structural biology, especially as the field moves toward the study of large macromolecular assemblies. We have developed the molecular dynamics flexible fitting (MDFF) method for combining high-resolution atomic structures with cryo-electron microscopy (cryo-EM) maps, that results in atomic models representing the conformational state captured by cryo-EM. The method has successfully been applied to the ribosome, a ribonucleoprotein complex responsible for protein synthesis. MDFF involves a molecular dynamics simulation in which a guiding potential, based on the cryo-EM map, is added to the standard force field. Forces proportional to the gradient of the density map guide an atomic structure, available from X-ray crystallography, into high-density regions of a cryo-EM map. In this paper we describe the necessary steps to set up, run, and analyze MDFF simulations and the software packages that implement the corresponding functionalities.

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Magnetoreception through cryptochrome may involve superoxide.

Ilia A. Solov'yov and Klaus Schulten. Magnetoreception through cryptochrome may involve superoxide. Biophysical Journal, 96:4804-4813, 2009.

In the last decades, it was demonstrated that many animal species orient in the Earth magnetic field. One of the best-studied examples is the use of the geomagnetic field by migratory birds for orientation and navigation. However, the biophysical mechanism underlying animal magnetoreception is still not understood. One theory for magnetoreception in birds invokes the so-called `radical pair' model. This mechanism involves a pair of reactive radicals, whose chemical fate can be influenced by the orientation with respect to the magnetic field of the Earth through Zeeman and hyperfine interactions. The fact that the geomagnetic field is weak, i.e., about 0.5 G, puts a severe constraint on the radical pair that can establish the magnetic compass sense. For a noticeable change of the reaction yield in a redirected geomagnetic field, the hyperfine interaction has to be as weak as the Earth field Zeeman interaction, i.e., unusually weak for an organic compound. Such weak hyperfine interaction can be achieved if one of the radicals is completely devoid of this interaction as realized in a radical pair containing an oxygen molecule as one of the radicals. Accordingly, we investigate here a possible radical pair-based reaction in the photoreceptor cryptochrome that reduces the protein's flavin group from its signalling state FADH to the inactive state FADH (which reacts to the likewise inactive FAD) by means of the superoxide radical, O. We argue that the spin dynamics in the suggested reaction can act as a geomagnetic compass and that the very low physiological concentration (nM-M) of otherwise toxic O is sufficient, even favorable, for the biological function.

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Simulations of membrane tubulation by lattices of amphiphysin N-BAR domains.

Ying Yin, Anton Arkhipov, and Klaus Schulten. Simulations of membrane tubulation by lattices of amphiphysin N-BAR domains. Structure, 17:882-892, 2009.

Membrane compartments of manifold shapes are found in cells, often sculpted by cellular proteins. In particular, proteins of the BAR domain superfamily participate in membrane sculpting processes in vivo and reshape also in vitro low-curvature membrane liposomes into high-curvature tubes and vesicles. Here we show by means of computer simulations totaling over 1 millisecond, how lattices involving parallel rows of amphiphysin N-BAR domains sculpt flat membranes into tubes. A highly detailed, dynamic picture of the 100-microsecond formation of membrane tubes by lattices of N-BAR domains is obtained. Lattice types inducing a wide range of membrane curvatures, with radii approximately 15 to 100 nm, are explored. The results suggest that multiple lattice types are viable for efficient membrane bending.

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Molecular dynamics simulations of membrane channels and transporters.

Fatemeh Khalili-Araghi, James Gumbart, Po-Chao Wen, Marcos Sotomayor, Emad Tajkhorshid, and Klaus Schulten. Molecular dynamics simulations of membrane channels and transporters. Current Opinion in Structural Biology, 19:128-137, 2009.

Membrane transport constitutes one of the most fundamental processes in all living cells with proteins as major players. Proteins as channels provide highly selective diffusive pathways gated by environmental factors, and as transporters furnish directed, energetically uphill transport consuming energy. X-ray crystallography of channels and transporters furnishes a rapidly growing number of atomic resolution structures, permitting molecular dynamics (MD) simulations to reveal the physical mechanisms underlying channel and transporter function. Ever increasing computational power today permits simulations stretching up to 1sec, i.e., to physiologically relevant time scales. Membrane protein simulations presently focus on ion channels, on aquaporins, on protein-conducting channels, as well as on various transporters. In this review we summarize recent developments in this rapidly evolving field.

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