Visualizing Compaction of Polysomes in Bacteria.

International audienceDuring protein synthesis, many translating ribosomes are bound together with an mRNA molecule to form polysomes (or polyribosomes). While the spatial organization of bacterial polysomes has been well studied in vitro, little is known about how they cluster when cellular conditions are highly constrained. To better understand this, we used electron tomography, template matching, and three-dimensional modeling to analyze the supramolecular network of ribosomes after induction of translational pauses. In Escherichia coli, we overexpressed an mRNA carrying a polyproline motif known to induce pausing during translation. When working with a strain lacking transfer-messenger RNA, the principle actor in the "trans-translation" rescuing system, the cells survived the hijacking of the translation machinery but this resulted in a sharp modification of the ribosomal network. The results of our experiments demonstrate that single ribosomes are replaced with large amounts of compacted polysomes. These polysomes are highly organized, principally forming hairpins and dimers of hairpins that stack together. We propose that these spatial arrangements help maintain translation efficiency when the rescue systems are absent or overwhelmed

Adaptive GPU-accelerated force calculation for interactive rigid molecular docking using haptics

Molecular docking systems model and simulate in silico the interactions of intermolecular binding. Haptics-assisted docking enables the user to interact with the simulation via their sense of touch but a stringent time constraint on the computation of forces is imposed due to the sensitivity of the human haptic system. To simulate high fidelity smooth and stable feedback the haptic feedback loop should run at rates of 500 Hz to 1 kHz. We present an adaptive force calculation approach that can be executed in parallel on a wide range of Graphics Processing Units (GPUs) for interactive haptics-assisted docking with wider applicability to molecular simulations. Prior to the interactive session either a regular grid or an octree is selected according to the available GPU memory to determine the set of interatomic interactions within a cutoff distance. The total force is then calculated from this set. The approach can achieve force updates in less than 2 ms for molecular structures comprising hundreds of thousands of atoms each, with performance improvements of up to 90 times the speed of current CPU-based force calculation approaches used in interactive docking. Furthermore, it overcomes several computational limitations of previous approaches such as pre-computed force grids, and could potentially be used to model receptor flexibility at haptic refresh rates

Computer Simulations Provide Guidance for Molecular Medicine through Insights on Dynamics and Mechanisms at the Atomic Scale

International audienceComputer simulations provide crucial insights and rationales for the design of molecular approaches in medicine. Several case studies illustrate how molecular model building and molecular dynamics simulations of complex molecular assemblies such as membrane proteins help in that process. Important aspects relate to build relevant molecular models with and without a crystal structure, to model membrane aggregates, then to link (dynamic) models to function, and finally to understand key disease-triggering phenomena such as aggregation. Through selected examples-including key signaling pathways in neurotransmission-the links between a molecular-level understanding of biological mechanisms and original approaches to treat disease conditions will be illuminated. Such treatments may be symptomatic, e.g. by better understanding the function and pharmacology of macromolecular key players, or curative, e.g. through molecular inhibition of disease-inducing molecular processes