High-performance analysis of biomolecular containers to measure small-molecule transport, transbilayer lipid diffusion, and protein cavities

Compartmentalization is a central theme in biology. Cells are composed of numerous membrane-enclosed structures, evolved to facilitate specific biochemical processes; viruses act as containers of genetic material, optimized to drive infection. Molecular dynamics simulations provide a mechanism to study biomolecular containers and the influence they exert on their environments; however, trajectory analysis software generally lacks knowledge of container interior versus exterior. Further, many relevant container analyses involve large-scale particle tracking endeavors, which may become computationally prohibitive with increasing system size. Here, a novel method based on 3-D ray casting is presented, which rapidly classifies the space surrounding biomolecular containers of arbitrary shape, enabling fast determination of the identities and counts of particles (e.g., solvent molecules) found inside and outside. The method is broadly applicable to the study of containers and enables high-performance characterization of properties such as solvent density, small-molecule transport, transbilayer lipid diffusion, and topology of protein cavities. The method is implemented in VMD, a widely used simulation analysis tool that supports personal computers, clouds, and parallel supercomputers, including ORNL’s Summit and Titan and NCSA’s Blue Waters, where the method can be employed to efficiently analyze trajectories encompassing millions of particles. The ability to rapidly characterize the spatial relationships of particles relative to a biomolecular container over many trajectory frames, irrespective of large particle counts, enables analysis of containers on a scale that was previously unfeasible, at a level of accuracy that was previously unattainable. Author summary The cell is the basic unit of life. Within the container of the cell, the many chemical reactions and biological processes essential to life are carried out simultaneously. Human and other eukaryotic cells include a variety of sub-containers, namely organelles, that provide separation between reactions and processes, and engender the chemical environments conducive to them. In order to understand how the cell works, researchers must study the functions of these containers. Molecular dynamics simulations can reveal important information about how biomolecular containers behave and control their enclosed environments, but the latter can be particularly challenging and expensive to measure. The challenge arises because simulation analysis software lacks awareness of the concepts of container “inside” and “outside.” The expense arises because tracking the many solvent molecules that make up a container’s environment requires significant computing power. We have developed a method that allows the simulation analysis software VMD to automatically detect the interior versus exterior of a container and quickly identify the solvent molecules found in each location. This versatile new feature enables researchers to characterize essential container properties using a relatively inexpensive calculation. Further, the method performs efficiently on supercomputers, allowing researchers to study massive container systems that include millions of particles.