Highlights of our Work

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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.
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 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 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.

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