Lessons Learned from Responsive Molecular Dynamics Studies of the COVID-19 Virus.

Over the past 18 months, the need to perform atomic detail molecular dynamics simulations of the SARS-CoV-2 virion, its spike protein, and other structures related to the viral infection cycle has led biomedical researchers worldwide to urgently seek out all available biomolecular structure information, appropriate molecular modeling and simulation software, and the necessary computing resources to conduct their work. We describe our experiences from several COVID-19 research collaborations and the challenges they presented in terms of our molecular modeling software development and support efforts, our laboratory's local computing environment, and our scientists' use of non-traditional HPC hardware platforms such as public clouds for large scale parallel molecular dynamics simulations.

Multiscale modeling and cinematic visualization of photosynthetic energy conversion processes from electronic to cell scales.

Conversion of sunlight into chemical energy, namely photosynthesis, is the primary energy source of life on Earth. A visualization depicting this process, based on multiscale computational models from electronic to cell scales, is presented in the form of an excerpt from the fulldome show Birth of Planet Earth. This accessible visual narrative shows a lay audience, including children, how the energy of sunlight is captured, converted, and stored through a chain of proteins to power living cells. The visualization is the result of a multi-year collaboration among biophysicists, visualization scientists, and artists, which, in turn, is based on a decade-long experimental-computational collaboration on structural and functional modeling that produced an atomic detail description of a bacterial bioenergetic organelle, the chromatophore. Software advancements necessitated by this project have led to significant performance and feature advances, including hardware-accelerated cinematic ray tracing and instanced visualizations for efficient cell-scale modeling. The energy conversion steps depicted feature an integration of function from electronic to cell levels, spanning nearly 12 orders of magnitude in time scales. This atomic detail description uniquely enables a modern retelling of one of humanity's earliest stories-the interplay between light and life.

Atoms to Phenotypes: Molecular Design Principles of Cellular Energy Metabolism.

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.

Atomic Detail Visualization of Photosynthetic Membranes with GPU-Accelerated Ray Tracing.

The cellular process responsible for providing energy for most life on Earth, namely photosynthetic light-harvesting, requires the cooperation of hundreds of proteins across an organelle, involving length and time scales spanning several orders of magnitude over quantum and classical regimes. Simulation and visualization of this fundamental energy conversion process pose many unique methodological and computational challenges. We present, in two accompanying movies, light-harvesting in the photosynthetic apparatus found in purple bacteria, the so-called chromatophore. The movies are the culmination of three decades of modeling efforts, featuring the collaboration of theoretical, experimental, and computational scientists. We describe the techniques that were used to build, simulate, analyze, and visualize the structures shown in the movies, and we highlight cases where scientific needs spurred the development of new parallel algorithms that efficiently harness GPU accelerators and petascale computers.

GPU-accelerated analysis and visualization of large structures solved by molecular dynamics flexible fitting.

Hybrid structure fitting methods combine data from cryo-electron microscopy and X-ray crystallography with molecular dynamics simulations for the determination of all-atom structures of large biomolecular complexes. Evaluating the quality-of-fit obtained from hybrid fitting is computationally demanding, particularly in the context of a multiplicity of structural conformations that must be evaluated. Existing tools for quality-of-fit analysis and visualization have previously targeted small structures and are too slow to be used interactively for large biomolecular complexes of particular interest today such as viruses or for long molecular dynamics trajectories as they arise in protein folding. We present new data-parallel and GPU-accelerated algorithms for rapid interactive computation of quality-of-fit metrics linking all-atom structures and molecular dynamics trajectories to experimentally-determined density maps obtained from cryo-electron microscopy or X-ray crystallography. We evaluate the performance and accuracy of the new quality-of-fit analysis algorithms vis-à-vis existing tools, examine algorithm performance on GPU-accelerated desktop workstations and supercomputers, and describe new visualization techniques for results of hybrid structure fitting methods.

Domain motion of individual F1-ATPase ß-subunits during unbiased molecular dynamics simulations.

F(1)-ATPase is the catalytic domain of F(1)F(o)-ATP synthase and consists of a hexameric arrangement of three noncatalytic α and three catalytic ß subunits. We have used unbiased molecular dynamics simulations with a total simulation time of 900 ns to investigate the dynamic relaxation properties of isolated ß-subunits as a step toward explaining the function of the integral F(1) unit. To this end, we simulated the open (ß(E)) and the closed (ß(TP)) conformations under unbiased conditions for up to 120 ns each using several samples. The simulations confirm that nucleotide-free ß(E) retains its open configuration over the course of the simulations. The same is true when the neighboring α subunits are included. The nucleotide-depleted as well as the nucleotide-bound isolated ß(TP) subunits show a significant trend toward the open conformation during our simulations, with one trajectory per case opening completely. Hence, our simulations suggest that the equilibrium conformation of a nucleotide-free ß-subunit is the open conformation and that the transition from the closed to the open conformation can occur on a time scale of a few tens of nanoseconds.