cellPACK: a virtual mesoscope to model and visualize structural systems biology

Johnson, Graham; Autin, Ludovic; Al-Alusi, Mostafa A; Goodsell, David S.; Sanner, Michel F.; Olson, Arthur J.

doi:10.1038/nmeth.3204

Cited by 135 publications

(133 citation statements)

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“…Virion particles were modeled using cellPACK, an open-source project (http://cellPACK.org) designed to assemble large-scale models from molecular building blocks, as previously described (45,46). With the number of spikes (10,49,127,214, and 330) and particle size (140 nm) provided as input, cellPACK randomly distributed spikes on the surface of the spherical particle.…”

Section: Antibodies and Cells Monoclonal Antibodies (Humanmentioning

confidence: 99%

“…Whereas nonrandom distributions of spikes have been reported with immature HIV-1 due to interaction between the gp41 CTT and Pr55 Gag (43,44), the random distribution with our hVLPs is largely consistent with these being mature particles and having a partial truncation in the CTT. Using a computational approach, cellPACK (45,46) (Fig. 6B), we modeled virions with a random distribution of 10, 49, 127, 214, and 330 spikes.…”

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confidence: 99%

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Dense Array of Spikes on HIV-1 Virion Particles

Stano

Leaman

Kim

et al. 2017

J Virol

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HIV-1 is rare among viruses for having a low number of envelope glycoprotein (Env) spikes per virion, i.e., ϳ7 to 14. This exceptional feature has been associated with avoidance of humoral immunity, i.e., B cell activation and antibody neutralization. Virus-like particles (VLPs) with increased density of Env are being pursued for vaccine development; however, these typically require protein engineering that alters Env structure. Here, we used instead a strategy that targets the producer cell. We employed fluorescence-activated cell sorting (FACS) to sort for cells that are recognized by trimer cross-reactive broadly neutralizing antibody (bnAb) and not by nonneutralizing antibodies. Following multiple iterations of FACS, cells and progeny virions were shown to display higher levels of antigenically correct Env in a manner that correlated between cells and cognate virions (P ϭ 0.027). High-Env VLPs, or hVLPs, were shown to be monodisperse and to display more than a 10-fold increase in spikes per particle by electron microscopy (average, 127 spikes; range, 90 to 214 spikes). Sequencing revealed a partial truncation in the C-terminal tail of Env that had emerged in the sort; however, iterative rounds of "cell factory" selection were required for the high-Env phenotype. hVLPs showed greater infectivity than standard pseudovirions but largely similar neutralization sensitivity. Importantly, hVLPs also showed superior activation of Env-specific B cells. Hence, high-Env HIV-1 virions, obtained through selection of producer cells, represent an adaptable platform for vaccine design and should aid in the study of native Env.IMPORTANCE The paucity of spikes on HIV is a unique feature that has been associated with evasion of the immune system, while increasing spike density has been a goal of vaccine design. Increasing the density of Env by modifying it in various ways has met with limited success. Here, we focused instead on the producer cell. Cells that stably express HIV spikes were screened on the basis of high binding by bnAbs and low binding by nonneutralizing antibodies. Levels of spikes on cells correlated well with those on progeny virions. Importantly, high-Env virus-like particles (hVLPs) were produced with a manifest array of well-defined spikes, and these were shown to be superior in activating desirable B cells. Our study describes HIV particles that are densely coated with functional spikes, which should facilitate the study of HIV spikes and their development as immunogens.KEYWORDS antigenicity, broadly neutralizing antibodies, envelope glycoprotein, fluorescence-activated cell sorting, HIV-1, vaccine design, virus-like particles, cellPACK, electron microscopy, viral infectivity H uman immunodeficiency virus type 1 (HIV-1) displays around 7 to 14 envelope (Env) spikes per virion (1-3). This low number of spikes is unusual for enveloped viruses in comparison to numbers for influenza virus (ϳ400 to 500 spikes), vesicular

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Section: Antibodies and Cells Monoclonal Antibodies (Humanmentioning

confidence: 99%

mentioning

confidence: 99%

Dense Array of Spikes on HIV-1 Virion Particles

Stano

Leaman

Kim

et al. 2017

J Virol

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“…Finally, high-throughput computing is also being used to integrate structural data in the construction of atomic-scale models of viruses, subcellular compartments, or even whole cells (69). The scale and complexity of these models requires the development of radically new visualization methods, bridging structural and systems biology (70).…”

Section: Protein Structuresmentioning

confidence: 99%

Visualization of Biomedical Data

O’Donoghue

Baldi

Clark

et al. 2018

Annu. Rev. Biomed. Data Sci.

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The rapid increase in volume and complexity of biomedical data requires changes in research, communication, and clinical practices. This includes learning how to effectively integrate automated analysis with high–data density visualizations that clearly express complex phenomena. In this review, we summarize key principles and resources from data visualization research that help address this difficult challenge. We then survey how visualization is being used in a selection of emerging biomedical research areas, including three-dimensional genomics, single-cell RNA sequencing (RNA-seq), the protein structure universe, phosphoproteomics, augmented reality–assisted surgery, and metagenomics. While specific research areas need highly tailored visualizations, there are common challenges that can be addressed with general methods and strategies. Also common, however, are poor visualization practices. We outline ongoing initiatives aimed at improving visualization practices in biomedical research via better tools, peer-to-peer learning, and interdisciplinary collaboration with computer scientists, science communicators, and graphic designers. These changes are revolutionizing how we see and think about our data.

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“…Far from being trivial, this point requires algorithms to fill a 3D space with cellular components, which should satisfy a number of experimental constraints to capture each compartment spatial ordering (Lučić et al 2013;Mahamid et al 2016;Danev and Baumeister 2017). CellPack, Chrom3D, and LipidWrapper are examples of software that address this first challenge and that might be employed to model the eukaryotic cell architecture (Durrant and Amaro 2014;Johnson et al 2015;Earnest et al 2017;Paulsen et al 2017).…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

Molecular simulations of cellular processes

Trovato

Fumagalli

2017

Biophys Rev

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It is, nowadays, possible to simulate biological processes in conditions that mimic the different cellular compartments. Several groups have performed these calculations using molecular models that vary in performance and accuracy. In many cases, the atomistic degrees of freedom have been eliminated, sacrificing both structural complexity and chemical specificity to be able to explore slow processes. In this review, we will discuss the insights gained from computer simulations on macromolecule diffusion, nuclear body formation, and processes involving the genetic material inside cell-mimicking spaces. We will also discuss the challenges to generate new models suitable for the simulations of biological processes on a cell scale and for cellcycle-long times, including non-equilibrium events such as the co-translational folding, misfolding, and aggregation of proteins. A prominent role will be played by the wise choice of the structural simplifications and, simultaneously, of a relatively complex energetic description. These challenging tasks will rely on the integration of experimental and computational methods, achieved through the application of efficient algorithms.

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cellPACK: a virtual mesoscope to model and visualize structural systems biology

Cited by 135 publications

References 48 publications

Dense Array of Spikes on HIV-1 Virion Particles

Dense Array of Spikes on HIV-1 Virion Particles

Visualization of Biomedical Data

Molecular simulations of cellular processes

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