Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

Exploring Bismuth Coordination Complexes as Visible-Light Absorbers: Synthesis, Characterization, and Photophysical Properties.

Bismuth-based coordination complexes are advantageous over other metal complexes, as bismuth is the heaviest nontoxic element with high spin-orbit coupling and potential optoelectronics applications. Herein, four bismuth halide-based coordination complexes [Bi2Cl6(phen-thio)2] (1), [Bi2Br6(phen-thio)2] (2), [Bi2I6(phen-thio)2] (3), and [Bi2I6(phen-Me)2] (4) were synthesized, characterized, and subjected to detailed photophysical studies. The complexes were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and NMR studies. Spectroscopic analyses of 1-4 in solutions of different polarities were performed to understand the role of the organic and inorganic components in determining the ground- and excited-state properties of the complexes. The photophysical properties of the complexes were characterized by ground-state absorption, steady-state photoluminescence, microsecond time-resolved photoluminescence, and absorption spectroscopy. Periodic density functional theory (DFT) calculations were performed on the solid-state structures to understand the role of the organic and inorganic parts of the complexes. The studies showed that changing the ancillary ligand from chlorine (Cl) and bromine (Br) to iodine (I) bathochromically shifts the absorption band along with enhancing the absorption coefficient. Also, changing the halides (Cl, Br to I) affects the photoluminescent quantum yields of the ligand-centered (LC) emissive state without markedly affecting the lifetimes. The combined results confirmed that ground-state properties are strongly influenced by the inorganic part, and the lower-energy excited state is LC. This study paves the way to design novel bismuth coordination complexes for optoelectronic applications by rigorously choosing the ligands and bismuth salt.

Exploring CRD mobility during RAS/RAF engagement at the membrane.

During the activation of mitogen-activated protein kinase (MAPK) signaling, the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF bind to active RAS at the plasma membrane. The orientation of RAS at the membrane may be critical for formation of the RAS-RBDCRD complex and subsequent signaling. To explore how RAS membrane orientation relates to the protein dynamics within the RAS-RBDCRD complex, we perform multiscale coarse-grained and all-atom molecular dynamics (MD) simulations of KRAS4b bound to the RBD and CRD domains of RAF-1, both in solution and anchored to a model plasma membrane. Solution MD simulations describe dynamic KRAS4b-CRD conformations, suggesting that the CRD has sufficient flexibility in this environment to substantially change its binding interface with KRAS4b. In contrast, when the ternary complex is anchored to the membrane, the mobility of the CRD relative to KRAS4b is restricted, resulting in fewer distinct KRAS4b-CRD conformations. These simulations implicate membrane orientations of the ternary complex that are consistent with NMR measurements. While a crystal structure-like conformation is observed in both solution and membrane simulations, a particular intermolecular rearrangement of the ternary complex is observed only when it is anchored to the membrane. This configuration emerges when the CRD hydrophobic loops are inserted into the membrane and helices α3-5 of KRAS4b are solvent exposed. This membrane-specific configuration is stabilized by KRAS4b-CRD contacts that are not observed in the crystal structure. These results suggest modulatory interplay between the CRD and plasma membrane that correlate with RAS/RAF complex structure and dynamics, and potentially influence subsequent steps in the activation of MAPK signaling.

TopoMS: Comprehensive topological exploration for molecular and condensed-matter systems.

We introduce TopoMS, a computational tool enabling detailed topological analysis of molecular and condensed-matter systems, including the computation of atomic volumes and charges through the quantum theory of atoms in molecules, as well as the complete molecular graph. With roots in techniques from computational topology, and using a shared-memory parallel approach, TopoMS provides scalable, numerically robust, and topologically consistent analysis. TopoMS can be used as a command-line tool or with a GUI (graphical user interface), where the latter also enables an interactive exploration of the molecular graph. This paper presents algorithmic details of TopoMS and compares it with state-of-the-art tools: Bader charge analysis v1.0 (Arnaldsson et al., 01/11/17) and molecular graph extraction using Critic2 (Otero-de-la-Roza et al., Comput. Phys. Commun. 2014, 185, 1007). TopoMS not only combines the functionality of these individual codes but also demonstrates up to 4× performance gain on a standard laptop, faster convergence to fine-grid solution, robustness against lattice bias, and topological consistency. TopoMS is released publicly under BSD License. © 2018 Wiley Periodicals, Inc.

Computational Lipidomics of the Neuronal Plasma Membrane.

Membrane lipid composition varies greatly within submembrane compartments, different organelle membranes, and also between cells of different cell stage, cell and tissue types, and organisms. Environmental factors (such as diet) also influence membrane composition. The membrane lipid composition is tightly regulated by the cell, maintaining a homeostasis that, if disrupted, can impair cell function and lead to disease. This is especially pronounced in the brain, where defects in lipid regulation are linked to various neurological diseases. The tightly regulated diversity raises questions on how complex changes in composition affect overall bilayer properties, dynamics, and lipid organization of cellular membranes. Here, we utilize recent advances in computational power and molecular dynamics force fields to develop and test a realistically complex human brain plasma membrane (PM) lipid model and extend previous work on an idealized, "average" mammalian PM. The PMs showed both striking similarities, despite significantly different lipid composition, and interesting differences. The main differences in composition (higher cholesterol concentration and increased tail unsaturation in brain PM) appear to have opposite, yet complementary, influences on many bilayer properties. Both mixtures exhibit a range of dynamic lipid lateral inhomogeneities ("domains"). The domains can be small and transient or larger and more persistent and can correlate between the leaflets depending on lipid mixture, Brain or Average, as well as on the extent of bilayer undulations.

Progressive Tree-Based Compression of Large-Scale Particle Data.

Scientific simulations and observations using particles have been creating large datasets that require effective and efficient data reduction to store, transfer, and analyze. However, current approaches either compress only small data well while being inefficient for large data, or handle large data but with insufficient compression. Toward effective and scalable compression/decompression of particle positions, we introduce new kinds of particle hierarchies and corresponding traversal orders that quickly reduce reconstruction error while being fast and low in memory footprint. Our solution to compression of large-scale particle data is a flexible block-based hierarchy that supports progressive, random-access, and error-driven decoding, where error estimation heuristics can be supplied by the user. For low-level node encoding, we introduce new schemes that effectively compress both uniform and densely structured particle distributions.

The confluence of machine learning and multiscale simulations.

Multiscale modeling has a long history of use in structural biology, as computational biologists strive to overcome the time- and length-scale limits of atomistic molecular dynamics. Contemporary machine learning techniques, such as deep learning, have promoted advances in virtually every field of science and engineering and are revitalizing the traditional notions of multiscale modeling. Deep learning has found success in various approaches for distilling information from fine-scale models, such as building surrogate models and guiding the development of coarse-grained potentials. However, perhaps its most powerful use in multiscale modeling is in defining latent spaces that enable efficient exploration of conformational space. This confluence of machine learning and multiscale simulation with modern high-performance computing promises a new era of discovery and innovation in structural biology.

Scalable Comparative Visualization of Ensembles of Call Graphs.

Optimizing the performance of large-scale parallel codes is critical for efficient utilization of computing resources. Code developers often explore various execution parameters, such as hardware configurations, system software choices, and application parameters, and are interested in detecting and understanding bottlenecks in different executions. They often collect hierarchical performance profiles represented as call graphs, which combine performance metrics with their execution contexts. The crucial task of exploring multiple call graphs together is tedious and challenging because of the many structural differences in the execution contexts and significant variability in the collected performance metrics (e.g., execution runtime). In this paper, we present Ensemble CallFlow to support the exploration of ensembles of call graphs using new types of visualizations, analysis, graph operations, and features. We introduce ensemble-Sankey, a new visual design that combines the strengths of resource-flow (Sankey) and box-plot visualization techniques. Whereas the resource-flow visualization can easily and intuitively describe the graphical nature of the call graph, the box plots overlaid on the nodes of Sankey convey the performance variability within the ensemble. Our interactive visual interface provides linked views to help explore ensembles of call graphs, e.g., by facilitating the analysis of structural differences, and identifying similar or distinct call graphs. We demonstrate the effectiveness and usefulness of our design through case studies on large-scale parallel codes.

Machine Learning-Driven Multiscale Modeling: Bridging the Scales with a Next-Generation Simulation Infrastructure.

Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence is especially true for a well-known cancer signaling pathway, where the membrane-bound RAS protein binds an effector protein called RAF. To capture the driving forces that bring RAS and RAF (represented as two domains, RBD and CRD) together on the plasma membrane, simulations with the ability to calculate atomic detail while having long time and large length- scales are needed. The Multiscale Machine-Learned Modeling Infrastructure (MuMMI) is able to resolve RAS/RAF protein-membrane interactions that identify specific lipid-protein fingerprints that enhance protein orientations viable for effector binding. MuMMI is a fully automated, ensemble-based multiscale approach connecting three resolution scales: (1) the coarsest scale is a continuum model able to simulate milliseconds of time for a 1 µm2 membrane, (2) the middle scale is a coarse-grained (CG) Martini bead model to explore protein-lipid interactions, and (3) the finest scale is an all-atom (AA) model capturing specific interactions between lipids and proteins. MuMMI dynamically couples adjacent scales in a pairwise manner using machine learning (ML). The dynamic coupling allows for better sampling of the refined scale from the adjacent coarse scale (forward) and on-the-fly feedback to improve the fidelity of the coarser scale from the adjacent refined scale (backward). MuMMI operates efficiently at any scale, from a few compute nodes to the largest supercomputers in the world, and is generalizable to simulate different systems. As computing resources continue to increase and multiscale methods continue to advance, fully automated multiscale simulations (like MuMMI) will be commonly used to address complex science questions.

AMM: Adaptive Multilinear Meshes.

Adaptive representations are increasingly indispensable for reducing the in-memory and on-disk footprints of large-scale data. Usual solutions are designed broadly along two themes: reducing data precision, e.g., through compression, or adapting data resolution, e.g., using spatial hierarchies. Recent research suggests that combining the two approaches, i.e., adapting both resolution and precision simultaneously, can offer significant gains over using them individually. However, there currently exist no practical solutions to creating and evaluating such representations at scale. In this work, we present a new resolution-precision-adaptive representation to support hybrid data reduction schemes and offer an interface to existing tools and algorithms. Through novelties in spatial hierarchy, our representation, Adaptive Multilinear Meshes (AMM), provides considerable reduction in the mesh size. AMM creates a piecewise multilinear representation of uniformly sampled scalar data and can selectively relax or enforce constraints on conformity, continuity, and coverage, delivering a flexible adaptive representation. AMM also supports representing the function using mixed-precision values to further the achievable gains in data reduction. We describe a practical approach to creating AMM incrementally using arbitrary orderings of data and demonstrate AMM on six types of resolution and precision datastreams. By interfacing with state-of-the-art rendering tools through VTK, we demonstrate the practical and computational advantages of our representation for visualization techniques. With an open-source release of our tool to create AMM, we make such evaluation of data reduction accessible to the community, which we hope will foster new opportunities and future data reduction schemes.

Asynchronous Reciprocal Coupling of Martini 2.2 Coarse-Grained and CHARMM36 All-Atom Simulations in an Automated Multiscale Framework.

The appeal of multiscale modeling approaches is predicated on the promise of combinatorial synergy. However, this promise can only be realized when distinct scales are combined with reciprocal consistency. Here, we consider multiscale molecular dynamics (MD) simulations that combine the accuracy and macromolecular flexibility accessible to fixed-charge all-atom (AA) representations with the sampling speed accessible to reductive, coarse-grained (CG) representations. AA-to-CG conversions are relatively straightforward because deterministic routines with unique outcomes are achievable. Conversely, CG-to-AA conversions have many solutions due to a surge in the number of degrees of freedom. While automated tools for biomolecular CG-to-AA transformation exist, we find that one popular option, called Backward, is prone to stochastic failure and the AA models that it does generate frequently have compromised protein structure and incorrect stereochemistry. Although these shortcomings can likely be circumvented by human intervention in isolated instances, automated multiscale coupling requires reliable and robust scale conversion. Here, we detail an extension to Multiscale Machine-learned Modeling Infrastructure (MuMMI), including an improved CG-to-AA conversion tool called sinceCG. This tool is reliable (∼98% weakly correlated repeat success rate), automatable (no unrecoverable hangs), and yields AA models that generally preserve protein secondary structure and maintain correct stereochemistry. We describe how the MuMMI framework identifies CG system configurations of interest, converts them to AA representations, and simulates them at the AA scale while on-the-fly analyses provide feedback to update CG parameters. Application to systems containing the peripheral membrane protein RAS and proximal components of RAF kinase on complex eight-component lipid bilayers with ∼1.5 million atoms is discussed in the context of MuMMI.

Effect of π···π Interactions of Donor Rings on Persistent Room-Temperature Phosphorescence in D4-A Conjugates and Data Security Application.

Organic room-temperature phosphorescence (RTP) materials with persistent RTP (PRTP) have attracted huge interest in inks, bioimaging, and photodynamic therapy. However, the design principle to increase the lifetime of organic molecules is underdeveloped. Herein, we show donor(D4)-acceptor(A) molecules (TOEPh, TOCPh, TOMPh, TOF and TOPh) with similar orientation of donor rings in aggregates that cause a large number of noncovalent interactions. We observed that TOEPh, TOCPh, TOMPh and TOF showed PRTP, whereas TOPh showed only phosphorescence emission (ΦP = ∼11%) with no PRTP property at ambient conditions. The spectroscopic and single-crystal X-ray analyses confirm the molecular assembly via J-aggregation with a face-to-face orientation of the donor rings. The crystal structure analysis (TOEPh, TOCPh, TOMPh, TOF) reveals that moderate π···π interactions (3.706 to 4.065 Å) between the donor rings cause the enhancement of the phosphorescence lifetime (26 to 245 ms), whereas the short phosphorescence lifetime (12 ms) of TOPh was observed because of the absence of π···π interactions. We found that TOEPh shows a long lifetime (245 ms) as compared to other derivatives because of the presence of ethoxy (-OEt) groups that enables spin-orbit coupling caused by strong lone pair (O)···π interactions present in the molecule. Utilizing the PRTP feature of TOEPh and the fluorescence emission of TOPh, we have shown data security applications in poly(methyl methacrylate).

Vector Field Decompositions Using Multiscale Poisson Kernel.

Extraction of multiscale features using scale-space is one of the fundamental approaches to analyze scalar fields. However, similar techniques for vector fields are much less common, even though it is well known that, for example, turbulent flows contain cascades of nested vortices at different scales. The challenge is that the ideas related to scale-space are based upon iteratively smoothing the data to extract features at progressively larger scale, making it difficult to extract overlapping features. Instead, we consider spatial regions of influence in vector fields as scale, and introduce a new approach for the multiscale analysis of vector fields. Rather than smoothing the flow, we use the natural Helmholtz-Hodge decomposition to split it into small-scale and large-scale components using progressively larger neighborhoods. Our approach creates a natural separation of features by extracting local flow behavior, for example, a small vortex, from large-scale effects, for example, a background flow. We demonstrate our technique on large-scale, turbulent flows, and show multiscale features that cannot be extracted using state-of-the-art techniques.

Visualizing Hierarchical Performance Profiles of Parallel Codes Using CallFlow.

Calling context trees (CCTs) couple performance metrics with call paths, helping understand the execution and performance of parallel programs. To identify performance bottlenecks, programmers and performance analysts visually explore CCTs to form and validate hypotheses regarding degraded performance. However, due to the complexity of parallel programs, existing visual representations do not scale to applications running on a large number of processors. We present CallFlow, an interactive visual analysis tool that provides a high-level overview of CCTs together with semantic refinement operations to progressively explore CCTs. Using a flow-based metaphor, we visualize a CCT by treating execution time as a resource spent during the call chain, and demonstrate the effectiveness of our design with case studies on large-scale, production simulation codes.

Efficient and Flexible Hierarchical Data Layouts for a Unified Encoding of Scalar Field Precision and Resolution.

To address the problem of ever-growing scientific data sizes making data movement a major hindrance to analysis, we introduce a novel encoding for scalar fields: a unified tree of resolution and precision, specifically constructed so that valid cuts correspond to sensible approximations of the original field in the precision-resolution space. Furthermore, we introduce a highly flexible encoding of such trees that forms a parameterized family of data hierarchies. We discuss how different parameter choices lead to different trade-offs in practice, and show how specific choices result in known data representation schemes such as zfp [52], idx [58], and jpeg2000 [76]. Finally, we provide system-level details and empirical evidence on how such hierarchies facilitate common approximate queries with minimal data movement and time, using real-world data sets ranging from a few gigabytes to nearly a terabyte in size. Experiments suggest that our new strategy of combining reductions in resolution and precision is competitive with state-of-the-art compression techniques with respect to data quality, while being significantly more flexible and orders of magnitude faster, and requiring significantly reduced resources.

Capturing Biologically Complex Tissue-Specific Membranes at Different Levels of Compositional Complexity.

Plasma membranes (PMs) contain hundreds of different lipid species that contribute differently to overall bilayer properties. By modulation of these properties, membrane protein function can be affected. Furthermore, inhomogeneous lipid mixing and domains of lipid enrichment/depletion can sort proteins and provide optimal local environments. Recent coarse-grained (CG) Martini molecular dynamics efforts have provided glimpses into lipid organization of different PMs: an "Average" and a "Brain" PM. Their high complexity and large size require long simulations (∼80 µs) for proper sampling. Thus, these simulations are computationally taxing. This level of complexity is beyond the possibilities of all-atom simulations, raising the question-what complexity is needed for "realistic" bilayer properties? We constructed CG Martini PM models of varying complexity (63 down to 8 different lipids). Lipid tail saturations and headgroup combinations were kept as consistent as possible for the "tissues'" (Average/Brain) at three levels of compositional complexity. For each system, we analyzed membrane properties to evaluate which features can be retained at lower complexity and validate eight-component bilayers that can act as reliable mimetics for Average or Brain PMs. Systems of reduced complexity deliver a more robust and malleable tool for computational membrane studies and allow for equivalent all-atom simulations and experiments.

Scalable Topological Data Analysis and Visualization for Evaluating Data-Driven Models in Scientific Applications.

With the rapid adoption of machine learning techniques for large-scale applications in science and engineering comes the convergence of two grand challenges in visualization. First, the utilization of black box models (e.g., deep neural networks) calls for advanced techniques in exploring and interpreting model behaviors. Second, the rapid growth in computing has produced enormous datasets that require techniques that can handle millions or more samples. Although some solutions to these interpretability challenges have been proposed, they typically do not scale beyond thousands of samples, nor do they provide the high-level intuition scientists are looking for. Here, we present the first scalable solution to explore and analyze high-dimensional functions often encountered in the scientific data analysis pipeline. By combining a new streaming neighborhood graph construction, the corresponding topology computation, and a novel data aggregation scheme, namely topology aware datacubes, we enable interactive exploration of both the topological and the geometric aspect of high-dimensional data. Following two use cases from high-energy-density (HED) physics and computational biology, we demonstrate how these capabilities have led to crucial new insights in both applications.

MemSurfer: A Tool for Robust Computation and Characterization of Curved Membranes.

Advances in simulation methodologies, code efficiency, and computing power have enabled larger, longer, and more-complicated biological membrane simulations. The resulting membranes can be highly complex and have curved geometries that greatly deviate from a simple planar state. Studying these membranes requires appropriate characterization of geometric and topological properties of the membrane surface before any local lipid properties, such as areas and curvatures, can be computed. We present MemSurfer, an efficient and versatile tool to robustly compute membrane surfaces for a wide variety of large-scale molecular simulations. MemSurfer works independent of the type of simulation and directly on 3D point coordinates. As a result, MemSurfer can handle a variety of membranes. Using Delaunay triangulations and surface parameterizations, MemSurfer not only computes common lipid properties of interest but also provides direct access to the membrane surface itself, allowing the user to potentially conceive and compute a variety of nonstandard properties. The software provides a simple-to-use Python API and is released open-source under a GPL3 license.

Biluminescence via Fluorescence and Persistent Phosphorescence in Amorphous Organic Donor(D4)-Acceptor(A) Conjugates and Application in Data Security Protection.

Purely organic biluminescent materials are of great interest due to the involvement of both singlet and long-lived triplet emissions, which have been rarely reported in bioimaging and organic light-emitting diodes. We show two molecules 3,4,5,6-tetraphenyloxy-phthalonitrile (POP) and 3,4,5,6-tetrakis- p-tolyloxy-phthalonitrile (TOP), in which POP was found to exhibit fluorescence and persistent room-temperature green phosphorescence (pRTGP) in the amorphous powder and crystal states. Both POP and TOP show aggregation-induced emission in a tetrahydrofuran-water mixture. We found in single-crystal X-ray analysis that intra- and intermolecular lp(O)···π interactions along with π(C = C)···π(C≡N), hydrogen bond (H-B), and C-H···π interactions induce a head-to-tail slipped-stack arrangement in POP. In addition, the X-ray structure of TOP with a slipped-stack arrangement induced by only π(C═C)···π(C≡N) and H-B interactions shows dim afterglow only in crystals. These indicate that more noncovalent interactions found in POP may reinforce relatively efficient intersystem crossing that leads to pRTGP. Given the unique green afterglow feature in amorphous powder of POP, document security protection application is achievable.