Advances in Human-Protein Interaction - Interactive and Immersive Molecular Simulations

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Chapter 5: Food Security

The current food system (production, transport, processing, packaging, storage, retail, consumption, loss and waste) feeds the great majority of world population and supports the livelihoods of over 1 billion people. Since 1961, food supply per capita has increased more than 30%, accompanied by greater use of nitrogen fertilisers (increase of about 800%) and water resources for irrigation (increase of more than 100%). However, an estimated 821 million people are currently undernourished, 151 million children under five are stunted, 613 million women and girls aged 15 to 49 suffer from iron deficiency, and 2 billion adults are overweight or obese. The food system is under pressure from non-climate stressors (e.g., population and income growth, demand for animal-sourced products), and from climate change. These climate and non-climate stresses are impacting the four pillars of food security (availability, access, utilisation, and stability)

FvNano: A Virtual Laboratory to Manipulate Molecular Systems

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A Multimodal VR Framework for Interactive Molecular Simulations

International audienceMolecular simulation is nowadays becoming a routine technique in structural biology. Recent progress along with increasingly widespread access to substantial computing power now enables the study of macromolecular systems in interactive time. Visual inspection of MD trajectories is a good way to quickly discover general trends and perform initial analysis.Interactive Molecular Simulation (IMS) provides visualisation of and interaction with a simulation in progress, as well as possible on-the-fly control over simulation settings. Yet, few simulation and visualisation programs implement these features or often lack functionalities such as dynamic “live” analysis tools or efficient rendering

MMB-GUI : a fast morphing method demonstrates a possible ribosomal tRNA translocation trajectory

Easy-to-use macromolecular viewers, such as UCSF Chimera, are a standard tool in structural biology. They allow rendering and performing geometric operations on large complexes, such as viruses and ribosomes. Dynamical simulation codes enable modeling of conformational changes, but may require considerable time and many CPUs. There is an unmet demand from structural and molecular biologists for software in the middle ground, which would allow visualization combined with quick and interactive modeling of conformational changes, even of large complexes. This motivates MMB-GUI. MMB uses an internal-coordinate, multiscale approach, yielding as much as a 2000-fold speedup over conventional simulation methods. We use Chimera as an interactive graphical interface to control MMB. We show how this can be used for morphing of macromolecules that can be heterogeneous in biopolymer type, sequence, and chain count, accurately recapitulating structural intermediates. We use MMB-GUI to create a possible trajectory of EF-G mediated gate-passing translocation in the ribosome, with all-atom structures. This shows that the GUI makes modeling of large macromolecules accessible to a wide audience. The morph highlights similarities in tRNA conformational changes as tRNA translocates from A to P and from P to E sites and suggests that tRNA flexibility is critical for translocation completion

MMB-GUI : a fast morphing method demonstrates a possible ribosomal tRNA translocation trajectory

Easy-to-use macromolecular viewers, such as UCSF Chimera, are a standard tool in structural biology. They allow rendering and performing geometric operations on large complexes, such as viruses and ribosomes. Dynamical simulation codes enable modeling of conformational changes, but may require considerable time and many CPUs. There is an unmet demand from structural and molecular biologists for software in the middle ground, which would allow visualization combined with quick and interactive modeling of conformational changes, even of large complexes. This motivates MMB-GUI. MMB uses an internal-coordinate, multiscale approach, yielding as much as a 2000-fold speedup over conventional simulation methods. We use Chimera as an interactive graphical interface to control MMB. We show how this can be used for morphing of macromolecules that can be heterogeneous in biopolymer type, sequence, and chain count, accurately recapitulating structural intermediates. We use MMB-GUI to create a possible trajectory of EF-G mediated gate-passing translocation in the ribosome, with all-atom structures. This shows that the GUI makes modeling of large macromolecules accessible to a wide audience. The morph highlights similarities in tRNA conformational changes as tRNA translocates from A to P and from P to E sites and suggests that tRNA flexibility is critical for translocation completion

Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of -1 Frameshifting by tRNA(Ser3)

In-frame decoding in the ribosome occurs through canonical or wobble Watson-Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet-triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read in a different register. There are many mechanisms to induce frameshifting, and most are insufficiently understood. One previously proposed mechanism is doublet decoding, in which only codon bases 1 and 2 are read by anticodon bases 34 and 35, which would lead to -1 frameshifting. In E. coli, tRNA(GCU)(Ser3) can induce -1 frameshifting at alanine (GCA) codons. The logic of the doublet decoding model is that the Ala codon's GC could pair with the tRNA(Ser3 ')s GC, leaving the third anticodon residue U36 making no interactions with mRNA. Under that model, a U36C mutation would still induce -1 frameshifting, but experiments refute this. We perform all-atom simulations of wild-type tRNA(Ser3), as well as a U36C mutant. Our simulations revealed a hydrogen bond between U36 of the anticodon and G1 of the codon. The U36C mutant cannot make this interaction, as it lacks the hydrogen-bond-donating H3. The simulation thus suggests a novel, non-doublet decoding mechanism for -1 frameshifting by tRNA(Ser3) at Ala codons

Formation of raft-like assemblies within clusters of influenza hemagglutinin observed by MD simulations.

International audienceThe association of hemagglutinin (HA) with lipid rafts in the plasma membrane is an important feature of the assembly process of influenza virus A. Lipid rafts are thought to be small, fluctuating patches of membrane enriched in saturated phospholipids, sphingolipids, cholesterol and certain types of protein. However, raft-associating transmembrane (TM) proteins generally partition into Ld domains in model membranes, which are enriched in unsaturated lipids and depleted in saturated lipids and cholesterol. The reason for this apparent disparity in behavior is unclear, but model membranes differ from the plasma membrane in a number of ways. In particular, the higher protein concentration in the plasma membrane may influence the partitioning of membrane proteins for rafts. To investigate the effect of high local protein concentration, we have conducted coarse-grained molecular dynamics (CG MD) simulations of HA clusters in domain-forming bilayers. During the simulations, we observed a continuous increase in the proportion of raft-type lipids (saturated phospholipids and cholesterol) within the area of membrane spanned by the protein cluster. Lateral diffusion of unsaturated lipids was significantly attenuated within the cluster, while saturated lipids were relatively unaffected. On this basis, we suggest a possible explanation for the change in lipid distribution, namely that steric crowding by the slow-diffusing proteins increases the chemical potential for unsaturated lipids within the cluster region. We therefore suggest that a local aggregation of HA can be sufficient to drive association of the protein with raft-type lipids. This may also represent a general mechanism for the targeting of TM proteins to rafts in the plasma membrane, which is of functional importance in a wide range of cellular processes

Innovative interactive flexible docking method for multi-scale reconstruction elucidates dystrophin molecular assembly

International audienceAt present, our molecular knowledge of dystrophin, the protein encoded by the DMD gene and mutated in myopathy patients, remains limited. To get around the absence of its atomic structure, we have developed an innovative interactive docking method based on the BioSpring software in combination with Small-angle X-ray Scattering (SAXS) data. BioSpring allows interactive handling of biological macromolecules thanks to an augmented Elastic Network Model (aENM) that combines the spring network with non-bonded terms between atoms or pseudo-atoms. This approach can be used for building molecular assemblies even on a desktop or a laptop computer thanks to code optimizations including parallel computing and GPU programming. By combining atomistic and coarse-grained models, the approach significantly simplifies the set-up of multi-scale scenarios. BioSpring is remarkably efficient for the preparation of numeric simulations or for the design of biomolecular models integrating qualitative experimental data restraints. The combination of this program and SAXS allowed us to propose the first high-resolution models of the filamentous central domain of dystrophin, covering repeats 11 to 17. Low-resolution interactive docking experiments driven by a potential grid enabled us to propose how dystrophin may associate with F-actin and nNOS. This information provides an insight into medically relevant discoveries to come