Highlights of our Work

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Lung surfactant protein, an influenza virus inhibitor

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Retroviruses are parasites that pose a major health threat to humans (for example in case of HIV) and other animals (for example in case of RSV, M-PMV, MLV, and many more viruses). After a retrovirus hijacks a cell, the infected cell produces multiple copies of the virus which are then released into the host's bloodstream. These newly released viruses must mature before they can infect other cells. A strategy for preventing virus spread is therefore, to lock the viral particles in their immature, non-infectious state. However, to render the immature virus an attractive target for structure-based drug development one needs to know its chemical structure. Unfortunately, the complexity and size of the viral particle ― an incomplete hexagonal shell with a size close to 100 nm ― have prevented the experimental determination of the chemical, namely atomic level, structure of the virus. As reported recently, a team of computational and experimental researchers have provided an atomic structure of the immature retroviral lattice for the Rous Sarcoma Virus. The multi-domain RSV model was derived through a combination of state-of-the-art modeling techniques, including, cryo-EM-guided homology modeling, large-scale molecular dynamics simulations using enhanced sampling capabilities available in NAMD, together with experimental measurements such as X-ray crystallography and a wealth of biochemical data. Particularly, the model reveals novel features of the packing and dynamics of the immature capsid protein with implications for the maturation process and confirms the stabilizing roles of the so-called upstream and downstream domains of the immature RSV. More information is available on our retrovirus website, and in a highlight video.
YidC : MDFF vs crystal

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Synthesis and placement of new proteins in a living cell poses a challenge for the cellular machinery, in particular in case of so-called membrane proteins. Starting with nothing more than a sequence of DNA, the cell has to translate the genetic code, stitch together the constituent amino acids, and then place the newly made protein where its function is needed, namely the cell membrane. To meet the challenge the cell employs a molecular machine for the synthesis of proteins, the ribosome (see the Dec. 2009 highlight on Managing the Protein Assembly Line ), as well as special proteins that translocate newly synthesized proteins out of the machine into the cell membrane (see the Feb. 2011 highlight on Placing New Proteins ). Depending on the complexity of the membrane protein insertion, different protein systems are used for the translocation, in most cases the systems involving complexes of several, even many, proteins. Now however, the structure and function of the simplest translocating protein system has been solved, which actually is made of only a single protein, called YidC. Despite its simplicity, structure determination of YidC was difficult, taking three decades. Successful structure determination was recently reported here, and involved the combination of cryo-electron microscopy, mutational experiments and computer simulations, the latter using NAMD, VMD and MDFF. The structure that was discovered shows a distinctive arrangement of five trans-membrane helices and reveals how a single copy of YidC interacts with the ribosome at the ribosomal tunnel exit and identifies a site for membrane protein insertion at the YidC protein-membrane lipid interface. The quality of this atomic model is validated by its close agreement with a recently published crystal structure of E. Coli YidC (here). More on our protein translocation website.
RNA translocation by Rho

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Many processes in living cells require molecular motors. Examples are transport of cargo within a cell, degrading misfolded proteins, and controlling gene expression. In the latter case acts a motor, called Rho, that moves along messenger RNA. The energy of the cell's motors stems from molecules of ATP that are converted to ADP, release thereby energy and drive motor action. How exactly this happens remained largely a mystery, despite decades of study and despite the availability of detailed molecular structures of the motors. A molecular dynamics study employing NAMD has achieved a great breakthrough in resolving the mechanism by which ATP-to-ADP conversion drives Rho to translocate along RNA. While molecular dynamics simulation, in principle, is well suited to explain Rho's motor action, the problem was that the action takes about a millisecond which is a time period beyond such simulations' reach. Employing new sampling methods, a recent publication, reported in new, complete and fascinating detail how Rho works. The simulations permitted literally to look under the hood of Rho's engine and see how it pulls itself along RNA and coordinates a cyclic and repeated motor action. It turned out that Rho, a ring of six identical protein subunits, engages in an ATP-to-ADP conversion-induced periodic motion of the subunits that pushes RNA electrostatically through the ring center. A completely surprising finding was the existence of coordination switches that make each ATP-to-ADP conversion lead to exactly one forward step along the RNA and keep the six subunits strictly synchronized, turning a randomly moving protein system into a well-behaved engine. More on our molecular motor website.
Multilevel Summation Method in NAMD

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Long-range electrostatic interactions control macromolecular processes within living cells as prominent charges appear everywhere, such as in DNA or RNA, in membrane lipid head groups, and in ion channels. Reliable and efficient description of electrostatic interactions is crucial in molecular dynamics simulations of such processes. Recently a new mathematical approach for calculating electrostatic interactions, known as multilevel summation method (MSM), has been developed and programmed into NAMD 2.10 as reported here. Compared to the earlier decades-long approach, the particle-mesh Ewald (PME) method, MSM provides more flexibility as it permits non-periodic simulations like ones with asymmetric charge distributions across a membrane or of a water droplet with a protein folding inside. Furthermore, MSM is ideally suited for modern parallel computers, running, for example, simulations of large virus particles. More information here.
bc1 complex embedded in membrane

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Most living cells acquire their energy through photosynthesis or respiration, both of which convert input energy (sun light or food, respectively) through coupled electron and proton transfer processes. A key role is played here by a protein, called the bc1 complex, that intermediately stores energy through the reaction of molecules of quinol into molecules of quinones, utilizing energy released to pump protons across an intracellular membrane. This reaction is initiated in the bc1 complex at the site of binding of the quinol molecule, but critical details about the physical mechanism leading to coupled electron-proton transfer are still unknown. A recent study, based on molecular modeling with NAMD and quantum chemistry calculations, investigated possible reaction mechanisms in case of the bc1 complex from the bacterium Rhodobacter capsulatus. The calculations suggest a novel configuration of amino acid residues responsible for quinol binding in the bc1 complex, and support a mechanism for coupled proton-electron transfer from quinol to iron-sulfur cluster. The study opens the door for a complete simulation description of the crucial role of the bc1 complex in bioenergetics. More about the bc1 complex can be found here.
VMD focal blur effect

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VMD light harvesting movie

The 1.9.2 release of VMD promises more insight and more beauty from use of an already powerful molecular visualization and analysis program. For more insight, VMD 1.9.2 exploits the power of parallel computers small and large to reduce analysis runtimes tremendously, as reported here, and here. VMD 1.9.2 strengthens collaboration between experimental and computational biologists in resolving atom-by-atom structure and dynamics of huge molecular assemblies arising in living cells by guiding interactively a match of computational model to experimental data, as reported here; this is achieved through quality-of-fit cross correlation to be computed rapidly using GPUs, the fastest means of modern calculation. Many new and updated tools, called plugins, developed by the VMD user community, are included in VMD 1.9.2, including force field parameterization, helix analysis, and normal mode plugins. VMD 1.9.2 incorporates a new remote control and works with Android phones and tablets. For more beauty, VMD 1.9.2 adds stunning interactive graphics on laptops. Such high quality graphics was previously available only on the most advanced computers, through powerful GPU-accelerated interactive ray tracing. Interactive ray tracing makes the task of getting a molecular image "just right" much easier than ever before; it also enables rendering of spectacular movies, turning scientists into great film directors. More details about VMD 1.9.2 features can be found here. See the light harvesting movie produced with VMD 1.9.2 here.
Ultrastable cellulosome complex

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Bacteria can make a living from a very wide range of food sources. This ability makes them, for example, essential symbionts in animal digestive tracts where they assist their hosts in breaking cellulose fibers up into compounds degradable by the animal metabolism. Today, human gut bacteria, part of the human microbiome, are one of the hottest research topics in medicine. Gut bacteria face a particularly tough job in the rumen of the cow where they digest hardy cellulose fibers of grasses. Key to the job, taking place in a constantly moving fluid, are molecular tentacles, so-called cellulosomes, on the surface of the symbiotic bacteria. The cellulosomes develop a tight grasp on and then effective cleavage of cellulose. In a joint experimental-computational study researchers have investigated how in case of the bacterium Ruminococcus flavefaciens cellulosomes are built in a modular way, with molecular modules easily binding and unbinding during cellulosome construction, but sticking extremely strongly together during cellulosome digestive activity. As reported recently, single molecule force microscopy and molecular dynamics simulations using NAMD could show that under strain the adhesive bonds between cellulosome modules become stronger than seen in any other biomolecular system, in fact, become nearly as tight as strong chemical bonds. While the experimental data revealed bond strength and other characteristics, simulations reproducing the observed data provided a detailed view of the adhesive bond at atomic resolution, thereby revealing the physical mechanism underlying the uniquely adhesive property of cellulosomes. Gut bacteria and cellulosomes can be employed in 2nd generation biofuel generation (see highlight Waste into Fuel). More on gut bacteria and cellulosomes on our biofuels website.
GlpT protein embedded in membrane

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The 2.10 release of the molecular dynamics program NAMD includes numerous enhancements to support simulations of massive supramolecular assemblies such as the HIV capsid (see highlight Elusive HIV-1 Capsid). A single such simulation of a hundred million atoms or more can utilize the tens of thousands of processors of petascale supercomputers thanks to recent advances in computational methodology reported here. Equally if not more significant, however, are advances in NAMD's implementation of multiple copy algorithms for enhanced sampling of smaller molecular systems as reported here. These algorithms have already allowed researchers studying the molecular machinery of living cells to reveal for the first time with NAMD mechanisms operating on timescales of milliseconds or longer, including the rotary action of the ubiquitous energy conversion complex ATP synthase and the inward to outward opening transition of the membrane transporter protein GlpT, shown in the accompanying animation. NAMD 2.10 also introduces multilevel summation, reported here, a major algorithmic advance enabling efficient long-range electrostatics for non-periodic and semi-periodic simulations. More on new features in the 2.10 release of NAMD can be found here.

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