Highlights of our Work

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Water droplet on top of an amorphous silica slab

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Bionanotechnology involves a marriage of two different materials: inorganic solids, like silica, and biomolecules, like DNA. The new combinations of materials have to be mastered on the laboratory bench as well as in computer simulations. On the bench, devices are manufactured and tested, in the simulations, they are imaged and designed. So far inorganic solids and biomolecules were simulated successfully, but only separately. To join the materials requires as much effort in simulations as on the bench. Even just the interaction of inorganic solids (like silica) with physiological solutions (water and ions) demands challenging descriptions of silica surface properties. As reported recently, researchers have now succeeded in describing accurately the wetting (by water) of amorphous silica, an essential material for nanoelectronics, clearing a major hurdle to simulating bionanotechnological devices, for example, those suggested for rapid and economical sequencing of DNA (see also Nov 2005 and Oct 2004 highlights). More on silica-water interaction here.
Opening of Lacy'S cytoplasmic cavity

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Escherichia coli are bacteria living in the intestines of mammals as part of their healthy gut flora, but also causing disease outside of the gut. The bacteria import from their environment nutriments, for example molecules of lactose, a sugar. For this purpose Escherichia coli employs in its cell membrane a protein channel, lactose permease, that translocates the sugar outside-in. This is the bacterium's "sweet tooth". To establish the unidirectional sugar transport, the bacterium utilizes an electrical potential maintained in the form of a trans-membrane proton gradient (more protons on the outer cellular than on the inner cellular side of the membrane). Protons, very small ions, that enter the channel from the outside one at a time, open the outer channel entrance. This permits access of lactose that gets bound inside the channel. Release of the proton to the cell interior closes the outer channel entrance and opens the inner channel entrance, such that the bound lactose can enter the cell. Despite extensive and elegant biochemical studies, the physical mechanism that couples unidirectional proton and sugar translocation is not yet known in detail. A crystallographic structure of lactose permease permitted now investigations into this mechanism by means of molecular dynamics simulations using NAMD. The simulations, reported in a recent publication, showed one step of the proton - sugar translocation, namely how binding and unbinding of the proton activates a spring-like bond, a so-called salt bridge, that closes and opens the inner channel exit. More information on the lactose permease project can be found here.
integrin and fibronectin complex

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Mammalian cells adhere to each other forming tissues. The adhesion is due to a network of proteins, so-called extracellular matrix proteins, "gluing" the cells together. The cell membranes are too soft to provide anchoring points for the extracellular matrix proteins; rather, the cells furnish on their outer surface specialized hooks for anchoring the extracellular matrix proteins. The hooks, in the form of surface proteins, are linked directly through the membranes to the intracellular cytoskeleton that stabilizes and shapes cells. Integrins are an important family of such surface proteins that form hooks specific for certain types of extracellular matrix proteins. The hooks are flexible, they can be open for contacts or closed, the switch being induced by signals from inside or outside the cell through interactions with other proteins. The interactions between integrins and extracellular matrix proteins are rather complex, as the proteins are composed of many subunits; fortunately, their overall structures are presently being solved through crystallography. In a recent report a major component of an integrin and an extracellular matrix protein have been investigated through molecular modeling using NAMD, including steered molecular dynamics. The study described in detail how the extracellular matrix protein induces a transition in integrin, potentially strengthening its adhesion property. See also previous highlights: the May 2006 "Killer's Entry Route", Dec 2004 "Snap Fastener on Biological Cells", Dec 2003 "Body's Glue", and Mar 2002 "Cells Sense Push and Pull". More on modeling of extracellular matrix proteins and integrins can be found here.
Motion of the LOV domain

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Most forms of life need to detect and respond to changes in their environment for survival and optimal growth. For this purpose organisms rely on receptors that are based on sensory proteins. In plants, several sensory proteins detect the ambient light for optimal exposure of their photosynthetic apparatus. One class of plant light sensors, the phototropins, influence photosynthesis and induce the transition between root and stem growth when seedlings emerge out of the ground. Induction is activated through several protein domains, two of which actually absorb light and for their sensitivity to light, oxygen, and voltage, are called LOV1 and LOV2 domains. Understanding the LOV domains' involvement in activation is important for studying the signaling mechanisms of other types of sensory proteins. Strangely, light absorbed by LOV domains is observed to lead to a distinct, but only very minute, structural change that does not explain how activation might come about. NAMD-based molecular dynamics simulations of the LOV domain have now revealed, as reported in a recent publication, that photoactivated LOV domains exhibit altered patterns of motion that can induce a signal for plant cells. More information may be found on our biological photoreceptors website.
Aquaporin and the Cambridge Five

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Sometimes analogies go a long way, surprisingly long.  Aquaporins are ubiquitous water channels in living cells, known to be tetrameric, each unit contributing one pore.  This much is certain and this is where an analogy begins, namely with a British spy ring that passed information to the Soviet Union during world war II and into the 1950s.  The ring is often referred to as the Cambridge Four since the spies, when recruited, were undergrads at Cambridge Trinity College and there were four of them (cryptonyms Stanley, Homer, Hicks, and Johnson).  But a Fifth Man was long suspected, yet never formally identified. Here the analogy continues: aquaporin was suspected to sport a fifth pore, supposedly at its center, where its four subunits join (hence known as the tetrameric pore).  Strong, but not yet completely conclusive,  evidence has now been put forward in a recent report that the central pore, actually quite plainly visible to the eye when aquaporins are inspected by molecular graphics, e.g., with VMD, is an ion channel gated by a common cellular signaling molecule, cGMP. The evidence stems from a combined computational (molecular dynamics using NAMD) and experimental (verifying computationally suggested mutants) study.  More information on the five pores can be found on our aquaporin website, more on the Cambridge Five here. But the analogy goes further. Today it is suspected that the Cambridge Five actually had more than five members and the same holds for the pores of aquaporin.  An ongoing investigation has lead to evidence that the further pore members conduct gases, for example carbon dioxide.  Hopefully, we will know one day with certainty all members of the Cambridge Five and all pores of aquaporin.
A ribosome and a much smaller titin I27 domain near a supercomputer and a laptop

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The computer processor is the workhorse of biomolecular modeling, with NAMD the plow to which a single processor or a team of thousands may be hitched. The recent release of NAMD 2.6 has extended the drawbar to harness the power of several thousand processors: 2000 on a Cray XT3 and 8,000 on an IBM Blue Gene/L. This permits the efficient simulation of an entire ribosome, the cell's protein factory, comprising 3,000,000 atoms when solvated. But the features and increased performance of NAMD 2.6 are also available to the scientist with only a laptop, on which a domain of the muscle protein titin (10,000 atoms solvated) can be readily simulated. NAMD has also become more versatile, supporting more force fields (OPLS, CHARMM with CMAP cross terms), calculating free energies, and executing customizable replica exchange simulations. In addition, NAMD can now be called from the structure analysis program VMD to calculate, for example, interaction energies between protein domains. Like increased horsepower in transportation, increased simulation power opens new routes, routes to study entire systems of biopolymers like the ribosome, not just one piece.
Molecular Motor Scooting along DNA

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DNA with its famous double helix structure stores the genetic information of all life forms known. In order that this information is read, the double helix needs to be first unwound and separated into single helices or strands. This is achieved by cellular motor proteins called helicases that operate on already separated DNA strands. The helicases specialize in unwinding and separating the DNA double helix by scooting along one of DNA's single strands against the point where the two strands merge into the double helix; pushing against this point unwinds and separates the double helix further. The helicases are driven by energy stored in molecules of ATP which bind to the protein and get released in their so-called hydrolyzed, lower energy, form. Based on atomic resolution structures, researchers have studied now one of the smallest helicases known, PcrA, from the electronic to the functional level carrying out quantum mechanical/molecular mechanical simulations (as described in a first publication), as well as a combination of classical molecular dynamics simulation, using NAMD, and stochastic modeling calculations (described in a second publication and a third publication). This resulted in an overall explanation of how ATP's hydrolysis powers helicase activity which has been reported in a fourth publication. The researchers discovered that PcrA moves with two "hands" along single stranded DNA; when ATP binds, one "hand" moves along the DNA; when ADP and Pi (the hydrolysis products of ATP) unbind, the other "hand" moves; through a molecular "trick" both "hands" move in the same direction. Amazingly, the hand movement arises mainly from an increase in random mobility of the hands. i.e., is not enforced. Physicists refer to the underlying mechanism as a ratchet mechanism that was indeed long suspected to drive molecular motors. Interestingly, the helicase motor is very closely related to a wide class of other biological motors, for example the FoF1-ATP synthase (see Mar 2004 and Nov 2004 highlights). For more information visit our helicase research website.
Ion permeation in K channels

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Biological cells, in particular neurons, maintain an inside-outside voltage gradient through active transport of ions (Na+, K+, Cl-, and others) across their membranes. The flow of the ions down their gradients through membrane channels is highly selective for each ion. The high selectivity permits nerve cells to signal each other through voltage spikes, which are produced through transient changes of channel conductivities for Na+ ions (channels open and close in about a ms) and K+ ions (channels open and close in about 10 ms). Crucial for the generation of voltage spikes is the selective, yet quick, conduction of ions, but as one knows from personal experience at border crossings, high selectivity and quick crossing seem to be mutually exclusive. Yet biological ion channels reconcile selectivity and speed. Prior experimental work, primarily that of year 2003 Nobelist MacKinnon, as well as computational work suggested how potassium channels achieve selectivity and speed. But until recently no high resolution atomic structure of a potassium channel was known in the open form and the suggested mechanism could not be tested under natural conditions through atomic level simulations. Last year's solution of the structure of the potassium channel Kv1.2 in its open form made it finally possible to simulate, using NAMD, the conduction of ions through Kv1.2 driven by a voltage gradient. The results reported recently confirmed indeed the high selectivity - high speed mechanism suggested earlier, namely a billiard-type motion of two and three ions, the last ion kicking the first ion out. The simulations revealed for the first time, through movies, the overall permeation process, including the jumps of ions between energetically favorable binding sites and the sequence of multi-ion configurations involved in permeation. More on our potassium channel web site.
VMD 1.8.5

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How far and how well molecular biologists can look into the living cell depends as much on microscopes and observations, as it depends on computers and their software. The premiere software for looking into the molecular world of the cell, VMD, has made a big leap forward in broadening the molecular horizon of life scientists through its new release, VMD 1.8.5. Researchers are offered now a fresh view through a modern unified bioinformatics environment, MultiSeq, combining sequence and structure analysis for proteins and amino acids. VMD, now literally more colorful, lets scientists quickly exchange VMD views through integration of BioCoRE, calculate APBS electrostatics maps, call on NAMD to calculate energies, build and mutate structures, determine easily force field parameters, and navigate through proteins with a flying camera. VMD 1.8.5, though only a minor version number different from the previous release, includes now many new structure building and analysis tools that make it easier for modelers to set up, run, and analyze computer simulations of biomolecules.

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Many proteins interact with gas molecules such as oxygen to perform their functions. In most cases, the gas molecules must reach sites buried deep inside the proteins that bind the molecules, with no obvious way in. Understanding how, for example, oxygen enters the protein, and mapping out which pathways it takes has been a long-standing challenge. As reported recently, computational biologists, inspired by previous work on the hydrogenase enzyme (see the September 2005 highlight), have developed a method, called implicit ligand sampling, that maps the pathways taken by gas molecules inside proteins. The mapping is determined by monitoring fluctuations of the protein, surprisingly, in the absence of the gas molecules. The mapping method is available in the most recent version of the program VMD used for structure and sequence analysis of proteins. The researchers applied the method to myoglobin, an oxygen-storing protein present in muscle cells, and determined detailed three-dimensional maps of oxygen and carbon monoxide pathways inside the protein (for more information see our web page). While some details of these pathways were already known from experiment, the implicit ligand maps revealed a large number of new pathways and suggest that oxygen enters myoglobin using many different entrance doors.
mechanical proteins

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The living state of biological cells manifests itself through mechanical motion on many length scales. Behind this motion are processes that generate and transform mechanical forces of various types. As with other cell functions, the machinery for cellular mechanics involves proteins. Their flexible structures can be deformed and restored, and are often essential for handling, transforming, and using mechanical force. For instance, proteins of muscle and the extracellular matrix exhibit salient elasticity upon stretching, mechanosensory proteins transduce weak mechanical stimuli into electrical signals, and so-called regulatory proteins force DNA into loops controlling, thereby, gene expression. In a recent review, the structure-function relationship of four protein complexes with well defined and representative mechanical functions has been described. The first protein system reviewed is titin, a protein that confers passive elasticity on muscle. The second system reviewed is the elastic extracellular matrix protein fibronectin and its cellular receptor integrin. The third protein system covered are the proteins cadherin and ankyrin involved in the transduction apparatus of mechanical senses and hearing. The last system surveyed is the lac repressor,  a protein which regulates gene expression by looping DNA. In each case, molecular dynamics simulations using NAMD provided insights into the physical mechanisms underlying the associated mechanical functions of living cells. (more on our mechanobiology web site).  
participants working on their clusters
For hard-working scientists, the task of maintaining a single desktop computer is an unwelcome distraction. But what if your work requires the power of ten or a hundred machines? Our recent series of workshops (Sep 2005, Nov 2005, Mar 2006, and Apr 2006) has given nearly one hundred participants hands-on experience installing and using low-cost Linux clusters. Students were taught to eliminate many sources of complexity, such as hard drives, and to automate what remained with cluster management software and a queueing system. Lectures on cluster design stressed the importance of knowing which applications would be run and choosing cost-effective hardware to meet those specific needs, as well as less-obvious aspects of cluster acquisition such as electrical power, cooling, and the purchasing process. After assembling and installing small four-node clusters, students ran both the molecular dynamics program NAMD and a more typical parallel application that they compiled from scratch. Most participants were motivated by concrete plans to build clusters for their own groups in the near future and felt better-equipped to do so following their experience.
Many proteins store gases like oxygen, carbon dioxide, and nitric oxide, or react with them. The gases are conducted into the protein through access routes that exist only in passing and as a result of a protein's fluctuations. Accordingly, access routes are difficult to establish, but researchers are now able to image gas access pathways inside proteins computationally. The new method has many implications for biotechnology and science (see our hydrogenase page and Sep 2005 highlight, "Hydrogen Fuel from Protein"). Imaging gas access systematically over whole protein families, e.g., the family of myoglobins, requires a large number of calculations that need to be run and monitored. The traditional means of doing so is very wasteful of the researchers' time. To solve this problem, NAMD-G, a grid-based automation engine for biomolecular simulations running the NAMD software, has been developed in a collaboration with the National Center for Supercomputing Applications (see recent paper). From the researchers' workstations, NAMD-G "farms out" a large number of calculations, in parallel, to supercomputers on the TeraGrid. NAMD-G monitors and manages multiple sequences of calculations at distant sites, and performs the necessary data transfers and backups on an as-needed basis. While the gas transport simulations provide a clear scientific driver for the development, NAMD-G is quite general and will aid any NAMD user with access to the TeraGrid. The result? Less time spent baby-sitting runs and more time for science.
Ionic concentration in MscS

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Bacterial cells, like those of Escherichia coli, protect themselves against sudden inside-out pressure differences that arise osmotically from changes in a cell's environment and that could burst the cellular envelop. The protection is achieved through so-called mechanosensitive channels in the cell membrane.  One such channel, that dissipates like a safety valve pressure differences across the Escherichia coli cell membrane, is contributed by the protein MscS.  Upon tension in the cell membrane, that can also be applied systematically in the laboratory, the channel opens and permits molecules to pass, as best measured through an ion current leaking through the stretched membrane.  MscS is a channel with a balloon-like filter,  the function of the latter being still a mystery  (see Nov 2004 highlight, "Japanese lantern protein").  Now computational biologists using NAMD teamed up with device engineers using BioMoca to study MscS as reported recently.  The team monitored the mysterious MscS computationally over several microseconds, a record time for protein simulations.  MscS was found to permit water passage, but to also exhibit strong electrostatic forces that focus ions streaming through its filter balloon and channel.  This suggests MscS to be both a hydrostatic and an electrical safety valve.  Even though now better known, MscS' entire function remains shrouded in mystery (more on our MscS web site).
anthrax-toxin-receptor complex

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Bacillus anthracis, the cause of anthrax, is one of the most lethal bacteria. In addition to its ability to infect animal and human cells, the bacterium attacks also the cells of the host's immune system, the so-called macrophages. For this purpose the anthrax bacterium releases three types of proteins, or toxins, into the blood stream of the host: protective antigen, lethal factor, and edema factor, referred to as PA, LF, and EF, respectively. LF and EF team up with PA, which transports them into a host macrophage cell. Once inside the cell, LF converts ATP to cyclic AMP, while EF disables MAPKKs, a family of signaling proteins. These attacks disrupt various cellular signaling pathways of macrophages and some other cells, essentially shutting down the host's immune system and often leading to death of the host. To invade macrophages, the toxins take an intricate entry route that involves binding to a cell receptor, capillary morphogenesis protein 2 (CMG2), inducing the cell to internalize the toxins in a bubble like membrane (endosome), the bubble wall being then punctured by seven PAs forming a channel upon a chemical (acidifying) trigger from the host; the channel permits then their lethal cargo, LFs and EFs, to slip into the cell. How exactly the PAs punctured the endosome wall remained a mystery. In a recent report the entry route has been resolved now in greater detail through molecular dynamics simulations using NAMD. The report reveals how acidic conditions in the endosome trigger conformational changes of the PA complex necessary for pore formation, and provides structural insights into the role of unusual interactions between the PAs and its receptor CMG2. Visit also our anthrax toxin webpage.
Frankfurt Workshop

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Computational tools, like the molecular graphics program VMD and molecular dynamics program NAMD, move rapidly from theoretical to experimental biology. To train researchers in the proper use of computational tools, a series of hands-on workshops was organized in the US and Australia in 2003-2005 (see July 2005 highlight). This year the first European hands-on workshop started a new generation of training with three novel features. First, the workshop addressed mainly bench scientists in need of computational methods. Second, the workshop introduced a key expansion of VMD that turned a mainly structurally oriented visualization program into a structure and sequence analysis program. This is achieved through a multiple sequence analysis tool in VMD, called multiseq. Third, all training material has been extended to multiple platforms and participants could bring their own laptops for the training sessions. As in the previous series, participants enjoyed workshop lectures that introduced concepts and good uses of biocomputing software, but were most enthusiastic about practical tutorials that provided opportunities to learn by example and to apply newly mastered tools to their own research. The participants carried all lecture material and software home on a DVD; others can obtain the same material through our web site (workshop lectures, tutorials, case studies, VMD, NAMD).
The lac repressor can fold a 385 bp-long DNA loop into 4 different conformations

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One of the most fascinating aspects of molecular biology is how objects of very different sizes are involved in the intricate biological machinery of living cells. A small protein may bind to DNA many times larger than itself and fold the DNA into a loop to regulate nearby genes. Understanding of such processes requires coupling of the dynamics of an individual protein to the dynamics of a long, looped DNA double helix. This can be achieved best through a so-called multi-scale approach that describes the protein motion at atomic resolution and the larger DNA in a less resolved manner as an elastic rod, i.e., a physical object behaving much like a twisted garden hose. Mathematical equations can be devised that capture the behavior of the DNA "hose" bent into a loop by a bound protein, predicting the conformation of the DNA as well as the energy that the protein has to muster to keep the DNA looped (DNA prefers energetically to be straight). A recent publication studies in detail mathematically and computationally the elastic rod model of DNA, taking for a case study the DNA loop folded by the lac repressor, a celebrated protein regulating the expression of DNA in E. coli. The study explores how physical characteristics built into the the elastic rod model influence the energy and conformation of looped DNA and describes the possible ways of coupling the looped DNA to all-atom protein simulations of the lac repressor or other regulatory proteins in order to achieve the multi-scale description of a protein-DNA complex.
SecY shown with a small polypeptide passing through its pore ring.

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Anyone who has attempted to fit a long piece of thread through a needle's eye realizes how difficult fitting something so small and flexible into such a small hole can be. Yet this action is carried out every second in every living cell. Flexible polypeptides, proteins, often have to cross a cellular membrane to get to their correct location, whether that location is an organelle within the cell or even outside of it. To accomplish this, they are pushed through a protein pore in an unfolded conformation much like a long string. The channel that accepts the string-like proteins, the protein translocon, allows only certain proteins to pass, while restricting access to molecules even much smaller than the macromolecular proteins. As reported in a recent publication, computer simulations using the molecular dynamics program NAMD helped to answer the question of how such a small channel could achieve this feat, demonstrating how the channel itself can be flexible yet resilient during a protein-crossing event and also elucidating in part how it can maintain such tight control over what is permitted to cross. For more information, see our Protein Translocation website.

Titin Z1Z2-Telethonin Complex

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Muscle fibers, through their so-called thick and thin filaments, contract and extend in doing their work. To render the fibers elastic and protect them from overstretching, the thick filaments are connected through a long and thin elastic protein, titin, to the base of the fibers. Titin, by far the longest protein in human cells, is a molecular bungee cord and, like such cord, must be affixed firmly to the base. How this is done was a mystery until crystallographers took the first atomic resolution image of the system: it turns out that two titins are spliced together at their ends like ropes. The splicing involves a third small protein, the titin-telethonin-titin system forming a U. The U apparently is thrown over a bollard-like cellular structure to hold the thick filaments much like boats are held by bollards and ropes at their mooring place. The crystallographers teamed up with computational biologists to investigate the mechanical strength of the titin - telethonin - titin cord by means of molecular dynamics simulations using NAMD. As reported recently, the cord has great mechanical strength due to an extended network of hydrogen bonds between beta-strands, common structural features in proteins, that in the present case form a sheet extending through all three proteins. This discovery explains how living cells can splice cellular proteins together through a system of hydrogen-bonded beta-strands that extend through several proteins. Interestingly, such beta-strands were seen previously in cases of diseases like Alzheimers where the feature leads, however, to pathological assembly of proteins. What needs to be understood now is how the telethonin glue is applied only to the right spots in the cell and how the cells prevent telethonin from splicing together the wrong proteins. For more information visit our titin-telethonin web page.


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Viruses, the cause of many diseases, are the smallest natural organisms known. They are extremely primitive and parasitic such that biologists refer to them as "particles", rather than organisms. Viruses contain in a protein shell, the capsid, their own building plan, the genome, in the form of DNA or RNA. Viruses hijack a biological cell and make it produce from one virus many new ones. Viruses have evolved elaborate mechanisms to infect host cells, to to produce and assemble their own components, and to leave the host cell when it bursts from viral overcrowding. Because of their simplicity and small size, computational biologists selected a virus for their first attempt to reverse-engineer in a computer program, NAMD, an entire life form, choosing one of the tiniest viruses for this purpose, the satellite tobacco mosaic virus. As described in a recent report, the researchers simulated the virus in a small drop of salt water, altogether involving over a million atoms. This provided an unprecedented view into the dynamics of the virus for a very brief time, revealing nevertheless the key physical properties of the viral particle as well as providing crucial information on its assembly. It may take still a long time to simulate a dog wagging its tail in the computer, but a big first step has been taken to simulate living organisms. Naturally, this step will assist modern medicine (more on our satellite tobacco mosaic virus web page).


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Lipoproteins are protein-lipid particles which circulate in the blood collecting cholesterol, fatty acids, and lipids. Low levels of one such lipoprotein particle, called high-density lipoprotein (HDL) or "good cholesterol", has been implicated in the increased risk of coronary heart disease. The ability of lipoproteins to transport lipid and cholesterol through the blood is amazing since these types of particles are not generally soluble in blood plasma. However, when HDLs assemble, proteins wrap themselves around the lipids and cholesterol, shielding the lipid tails from the aqueous environment. Native HDL exhibit a variety of shapes and sizes, for example forming a discoidal particle. Conventional high-resolution imaging techniques, such as NMR and X-ray crystallography, cannot resolve how lipid and cholesterol are being accommodated by HDL, but the assembly and geometry of HDL discs can be captured using computer simulations. Unfortunately, the long time scales required for HDL assembly was a major stumbling block. Now a new simulation method, coarse-grained modeling in conjunction with the molecular dynamics program NAMD, has permitted the simulation of HDL assembly as recently reported. The simulations show that lipids quickly aggregate into a bilayer from their initial spherical "micelle" shape and that the two proteins subsequently attach to either side forming a belt surrounding the lipid core. For more information see HDL & nanodisc and coarse-grained modeling.

Gating of Aquaporins

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Your favorite flower pot would not survive a weekend in your office without watering, if it wasn't for a sophisticated cellular mechanism evolved in land plants to conserve water under drought conditions. Water exchange between cells and their environment is facilitated by a group of highly specialized membrane proteins called aquaporins. Although present in all life forms, plants are particularly dependent on their function. While in most species these channels function as always-open "cellular pipes" allowing water in and out of the cell, in plants they evolved into "cellular faucets" whose water permeability can be controlled by the cell. Nearly all plant aquaporins can be gated in response to drought or even flooding conditions, through basic biochemical signals, e.g., phosphorylation and change of pH. A recent Nature paper reporting a collaborative study between crystallographers who succeeded in solving the first structure of a plant aquaporin from spinach, and modelers provides the most detailed view of the mechanism of gating for a membrane channel. Molecular dynamics simulations of the channel performed by NAMD reveals a dual gating mechanism in which phosphorylation of certain protein residues unleashes a long cytoplasmic loop that physically blocks water access to the pore. More information on aquaporin research can be found here.


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Molecular modeling with NAMD (NAnoscale Molecular Dynamics) promises to become a key methodology for research and development in bionanotechnology. Molecular modeling provides nanoscale images at atomic and even electronic resolution, predicts the nanoscale interaction of yet unfamiliar combinations of biological and inorganic materials, and can evaluate strategies for redesigning biopolymers for nanotechnological uses. The methodology's value has been reviewed for three uses in bionanotechnology. The first involves the use of single-walled carbon nanotubes as biomedical sensors where a computationally efficient, yet accurate description of the influence of biomolecules on nanotube electronic properties and a description of nanotube - biomolecule interactions were developed; this development furnishes the ability to test nanotube electronic properties in realistic biological environments (see Dec 2005 highlight). The second case study involves the use of nanopores manufactured into electronic nanodevices based on silicon compounds for single molecule electrical recording, in particular, for DNA sequencing. Here, modeling combining classical molecular dynamics, material science, and device physics, describes the interaction of biopolymers, e.g., DNA, with silicon nitrate and silicon oxide pores, furnishes accurate dynamic images of pore translocation processes, and predicts signals (see Nov 2005 and Oct 2004 highlights). The third case involves the development of nanoscale lipid bilayers for the study of embedded membrane proteins and cholesterol. Molecular modeling tested scaffold proteins, redesigned lipoproteins found in mammalian plasma that hold the discoidal membranes in shape, and predicted the assembly as well as final structure of the nanodiscs (see Feb 2005 highlight). In entirely new technological areas like bionanotechnology qualitative concepts, pictures, and suggestions are sorely needed; the three exemplary applications document that molecular modeling can serve as a critical "imaging" method for bionanotechnology, even though it may still fall short on quantitative precision.

FG nucleoporin binding to importin-β

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Eukaryotic cells envelop their genetic material in the cell nucleus whose boundary contains numerous pores. Only small molecules can pass through these nuclear pores unhindered. For all larger ones, passage is highly selective and controlled. The control involves import and export proteins (transport receptors) that load and release cargo on the proper side of the nucleus upon interaction with signaling proteins. Researchers are presently solving the structure of the nuclear pore and its transport receptors with increasing resolution, and the first atomic level investigation into the mechanism of nuclear pore selectivity has recently been reported [paper]. The study inspected the interaction between the transport receptor importin-β with key nuclear pore proteins that appear disordered near the center of the pore and contain characteristic phenylalanine-glycine sequence repeats. Molecular dynamics simulations using NAMD and analyzed using VMD revealed a key insight into the selectivity mechanism. The simulations showed that the key sequences of the repeat proteins interact strongly with certain spots on the surface of importin-β. The study confirmed spots that had previously been identified experimentally and, moreover, found numerous binding spots not yet seen in experiment. Further experiments and simulations promise an understanding of the selectivity of entry and exit from the nucleus, a key element of the cell's genetic control. For more information see our nuclear pore complex webpage.

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