Highlights of our Work

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Rotatory catalysis in V1-ATPase

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Living cells employ an intricate network of biochemical processes for the conversion of solar energy or nutrients into energy-rich Adenosine Tri Phosphate (ATP) molecules. From bacteria to fungi, plants, and animals, ATP serves as the universal energy currency of life, fueling the processes cells need to survive and function. Over the course of a day, an individual will typically use the equivalent of his or her bodyweight in ATP; however, the human body carries only a small amount of the molecule at any one time. That means cells must constantly recycle or replenish the ATP molecules, relying on a highly efficient motor protein called ATP synthase to do the job. Given its ubiquitous role in photosynthesis and respiration, efficiency of the ATP synthase motor has been a focus of intense biochemical investigations over the past three decades, which included Boyer and Walker's Nobel Prize-winning contributions in 1997. Yet, connection between the Chemistry of ATP dissociation and Physics of ATP synthase motor-action remained elusive. A recent study based on molecular dynamics simulations with NAMD reveals the working principles of V-type ATP synthase in atomic resolution. Swiveling motions in the protein ring were captured together with rubber band-like elasticity of the motor's central stalk. This swiveling motion of the ring when paired with the stalk absorbs about 75 percent of the energy released during ATP hydrolysis, showcasing a molecular design that underlies the molecular motor's remarkable energy-conversion efficiency. More on ATPase here and here.

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This year, the Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry to Jacques Dubochet, Joachim Frank, and Richard Henderson "for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution". We are pleased to celebrate this great triumph for structural biology along with the well-deserved recognition of the Center's long-time collaborator and friend, Joachim Frank. Our center has a long tradition in developing computational methods that enable scientists to build atomistic models of biomolecules. Molecular Dynamics Flexible Fitting (MDFF), a method developed in close collaboration with Joachim Frank and his group, reconciles high resolution data from X-ray crystallography and functional information from cryo-electron microscopy (cryo-EM). MDFF utilizes molecular dynamics to "naturally" fit each atom into a cryo-EM map. In less than a decade since its development, MDFF has proved instrumental in studying biomolecular systems. A selected list of publications employing MDFF both by our group and others can be found here.
Protein recycling is a key process crucial to a wide spectrum of regulatory processes within living cells. The executive player in this process is a molecular machine called the proteasome, which both unfolds and chops superfluous proteins into smaller pieces that will be used as raw building materials for new proteins. Given its critical role, the proteasome is involved in multiple human diseases, and it serves as a perfect target for a plethora of different drugs, most prominently, those commonly used in chemotherapy of cancer. With the goal of understanding how these drugs work and paving the way for designing even better drugs with less side effects, a recent collaborative study with W. Baumeister (MPI Munich) combined molecular dynamics flexible fitting (MDFF) with de novo structure prediction algorithms to derive four structural models from cryo-electron microscopy densities of the proteasome in different conformational states. These models provide the first atomic insights as to how ATP hydrolysis in the engine of the proteasome (cyan) unwinds proteins and steers them towards the degradation chamber (red). More information is available on our proteasome website. Easy access to our modeling techniques is provided through QwikMD.
Outward-faceing model of P-glycoprotein

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One of the most common mechanisms by which cancer and microbial cells develop resistance against chemotherapeutic agents is to express a large number of specialized transporter proteins in their cellular membrane that use the universal cellular energy of ATP to actively pump the drug molecules to the outside. P-glycoprotein, a prominent member of such molecular "vacuum cleaners" and responsible for multidrug resistance (MDR) in a wide variety of cancer types, accomplishes its role by undergoing large-scale structural transitions in the cellular membrane through which it effectively moves drug molecules from one side of the membrane to the other. In a recent collaborative publication in Nature with leading experimental groups at Vanderbilt and Virginia, and employing advanced molecular modeling and simulation techniques implemented in NAMD, a robust structural model was developed for the unknown outward-facing state of P-glycoprotein, allowing a full structural description of the transport cycle, and a novel mode of energy transduction. Further details of the study can be found here.
Proton-coupled electron transfer at the bc1 complex

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Cellular respiration and photosynthesis are the primary energy production mechanisms for sustaining life on earth. Both processes use input energy (food or sunlight) to drive coupled electron and proton transfer reactions, thus replenishing the electrical charge of the cellular membrane, which in turn is used to produce ATP - the universal fuel for all cellular activities. A key step involved in both bacterial photosynthesis and mitochondrial respiration is mediated by a specialized protein complex, the bc1 complex, which seizes the energy released from interconversion of quinol and quinone to pump protons across the bioenergetic membrane. A recent study, combining molecular simulations performed with NAMD and quantum chemical calculations, unveiled the coupled nature of the proton and electron transfer reactions in the quinol binding site of the bc1 complex from a photosynthetic bacterium at an unprecedented level and described the role of key mechanistic elements. More about the bc1 complex can be found here.
Journal of Physical Chemistry published a Memorial Issue ..." />
Proton-coupled electron transfer at the bc1 complex

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On April 20th, the Journal of Physical Chemistry published a Memorial Issue in honor of Klaus Schulten gathering more than 60 research articles. Klaus was an undisputed leader in theoretical and computational biophysics, recognized by his peers for his immense contribution to the field, and having devoted his entire career to establish the mechanisms that underlie cellular processes using the laws of physics. Originally planned to be a Festschrift to celebrate Klaus's achievements on his 70th birthday, the Memorial Issue initiative immediately triggered a unanimous positive response from friends, academic colleagues and longtime collaborators across the world. The many contributions assembled in the Memorial Issue of the Journal of Physical Chemistry lie at the confluence of theory and experiment, and cover a broad gamut of topics that were dear to Klaus, ranging from photosynthesis to molecular machines and membrane proteins. We gratefully acknowledge the many authors of the Memorial Issue, who enthusiastically accepted to pay one last homage to Klaus through contributions of very high scientific quality.
NAMD provides major enhancements in ..." />
NAMD Goes Quantum

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The 2.12 release of the molecular dynamics program NAMD provides major enhancements in performance, flexibility, and accuracy, complementing the greatly enhanced usability provided by the QwikMD GUI released in VMD 1.9.3. NVIDIA GPU-accelerated simulations with NAMD 2.12 are up to three times as fast as 2.11, particularly for implicit solvent simulations and single-node simulations of smaller systems. NAMD 2.12 is also optimized for the new Intel Xeon Phi KNL processors found in Argonne Theta, NERSC Cori, and TACC Stampede 2. NAMD 2.12 builds on the asynchronous multi-copy scripting capabilities introduced in NAMD 2.11 with the ability to modify and reload the molecular structure, enabling development of grand canonical and constant pH ensemble methods, as well as an optional Python interface for advanced on-the-fly analysis. Finally, NAMD 2.12 provides a complete, no-recompilation-needed interface for hybrid QM/MM with both the semi-empirical code MOPAC and the ab initio/DFT code ORCA. More on new features in the 2.12 release of NAMD can be found here. NAMD is available free-of-charge as source code, precompiled binaries, pre-installed at supercomputer centers, and now jointly with VMD as one-click interactive molecular modeling on the Amazon cloud.
VMD brings many advances that help researchers prepare, ..." />
VMD 1.9.3 release incorporates QwikMD, many rendering features.

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The latest release of VMD brings many advances that help researchers prepare, analyze, and visualize molecular simulations. The new QwikMD plugin streamlines key simulation preparation and analysis tasks, and guides users in the creation of reusable simulation workflows and protocols. VMD now includes several advanced features for parallel analysis and visualization of cellular-scale simulations, as reported here, and here. VMD 1.9.3 strengthens collaboration between experimental and computational biologists by supporting a broader range of experimental density map image formats, such as those used in cryo-electron tomography. Many updated plugins are included in VMD 1.9.3, including tools for analysis of free energy perturbation simulations, MDFF hybrid structure fitting, ffTK force field parameterization, and normal mode analysis. VMD 1.9.3 adds support for new hardware and operating system platforms including IBM OpenPOWER (ORNL Summit), a variety of GPU-accelerated ARM SoCs, the Amazon AWS EC2 cloud, and most recently, the Intel Xeon Phi Knight's Landing many-core CPU (TACC Stampede 2, Argonne Theta). The VMD 1.9.3 release adds stunning graphics produced using interactive ray tracing using the latest multi-core CPUs and GPU accelerators, enabling 360-degree panoramic movie rendering for VR headsets, as reported here, and here. 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 for communication of scientific results. A VR movie rendering tutorial assists users with the steps required in rendering and encoding VR movies for upload to YouTube for display using VR headsets such as Google Cardboard, Oculus Rift, and GearVR. More details about VMD 1.9.3 features can be found here.
Ion permeation in P2X receptor

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ATP, a ubiquitously prevalent biomolecule, which is best known for being the principal energy source for a living cell, also plays a crucial role in inter-cellular communication, thus acting as a signaling molecule. One of the major receptors in this signaling cascade are the P2X receptors which are trimeric, non-selective cation channel activated by ATP and responsible for key processes such as muscle contraction, inflammatory response, pain, and even taste signal transduction. As a result of their extensive prevalence and important implications in human physiology, P2X receptors serve as important pharmacological targets for cardiovascular, neuronal, and inflammatory diseases. In a recent collaborative study with experimental structural biologists, molecular dynamics simulations of a membrane-embedded model of a P2X receptor performed with NAMD were used to reveal intricate details of the ion permeation mechanism and pathway. Surprisingly, it was observed that one half of the ion permeation pathway is composed of lipids on one side and of the protein residues on the other side, a novel design for an ion translocation pore. The study demonstrates yet another active functional role for lipids in membrane protein function, further emphasizing the importance of lipid protein interactions in biological processes. More details can be found here.
bc1 complex embedded in membrane

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Photosynthetic organisms have been optimized by over two billion years of evolution into energy-harvesting machines that surpass the efficiency of man-made solar devices. Employing a network of hundreds of proteins, these organisms transform energy from the incident sunlight into ATP molecules - the universal fuel for sustaining cellular activities. A key step in the conversion of solar energy into ATP involves shuttling of negative charges or electrons between widely separated sites on the cell membrane. This membrane-wide charge transportation is accomplished by the cytochrome c family of proteins. Cytochrome c finds and docks to an electron donor protein, accepts the electron and unbinds as a result of it, and afterwards finds an electron acceptor protein, docks to it to deliver the electron and unbinds to repeat the sequence. Given its ubiquitous role in photosynthesis and respiration, the recognition, binding and unbinding mechanism of cytochrome c have been a focus of intense biochemical investigations over the past three decades. However, little is deciphered on the details of cytochrome c activity. A recent study based on molecular dynamics simulations with NAMD reveals the working principles of cytochrome c in atomic resolution. The calculations suggest that electrostatic forces drive the cytochrome c binding, and enable membrane-wide electron transfer. More about the cytochrome c protein can be found here.

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