bioRxiv Science⌕ Search

bioRxiv · 10.1101/2024.01.13.575515

ArborSim: Articulated, branching, OpenSim routing for constructing models of multi-jointed appendages with complex muscle-tendon architecture

Abstract

Computational models of musculoskeletal systems are essential tools for understanding how muscles, tendons, bones, and actuation signals generate motion. In particular, the OpenSim family of models has facilitated a wide range of studies on diverse human motions, clinical studies of gait, and even non-human locomotion. However, biological structures with many joints, such as fingers, necks, tails, and spines, have been a longstanding challenge to the OpenSim modeling community, especially because these structures comprise numerous bones and are frequently actuated by extrinsic muscles that span multiple joints--often more than three--and act through a complex network of branching tendons. Existing model building software, typically optimized for limb structures, makes it difficult to build OpenSim models that accurately reflect these intricacies. Here, we introduce ArborSim, customized software that efficiently creates musculoskeletal models of highly jointed structures and can build branched muscle-tendon architectures. We used ArborSim to construct toy models of articulated structures to determine which morphological features make a structure most sensitive to branching. By comparing the joint kinematics of models constructed with branched and parallel muscle-tendon units, we found that the number of tendon branches and the number of joints between branches are most sensitive to branching modeling method--notably, the differences between these models showed no predictable pattern with increased complexity. As the proportion of muscle increased, the kinematic differences between branched and parallel models units also increased. Our findings suggest that stress and strain interactions between distal tendon branches and proximal tendon and muscle greatly affect the overall kinematics of a musculoskeletal system. By incorporating complex muscle-tendon branching into OpenSim models using ArborSim, we can gain deeper insight into the interactions between the axial and appendicular skeleton, model the evolution and function of diverse animal tails, and understand the mechanics of more complex motions and tasks.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Fu, X., Withers, J., Miyamae, J., Moore, T.. 2024-01-15. ArborSim: Articulated, branching, OpenSim routing for constructing models of multi-jointed appendages with complex muscle-tendon architecture. https://doi.org/10.1101/2024.01.13.575515

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Mechanism of molecular recognition revealed through dynamic drug binding pathways to SARS-CoV-2 main protease

Characterization of drug-binding pathways remains experimentally limited by transient intermediates and computationally challenging due to long timescales intractable for conventional molecular dynamics. To address these challenges, we combined solution NMR titrations with weighted ensemble (WE) enhanced sampling simulations to resolve atomistic pathways of nirmatrelvir binding to the SARS-CoV-2 main protease. NMR titration revealed residue-dependent heterogeneity spanning fast, intermediate, and slow exchange regimes. WE simulations complement the NMR by providing insights into unassigned residues and adding time-resolved and three-dimensional structural context. We map key interactions along two distinct binding pathways, provide dynamic explanations for residues involved in resistance, and capture unique backbone conformations compared to those sampled in unbound or bound states. Our comprehensive binding model is consistent with a combined conformational selection and induced fit mechanism in which early transient contacts are made with residues E47 and L50 and allosteric motions are centered around residue V204 of the distal domain. This synergistic application of WE and titration NMR enables a more comprehensive characterization of drug binding than either method alone, providing an integrated framework that may have broader applicability to defining structure-kinetic relationships and guiding design of next-generation inhibitors.

biophysics↗

Fibers and Glasses are Competing Material States in FUS Protein Condensation

Dense, well-ordered material states of proteins form the amyloid fibers that are a hallmark of neurodegenerative disease in the brain. Beyond forming amyloid fibers, some of these proteins can also adopt other material states termed condensates which are initially liquid-like but evolve to a soft, glassy phase. Fiber growth requires a large supply of monomers and, thus, it is often speculated that fibers emerge from within a dense condensate as it ages and its microscopic dynamics slow into a glassy state. Here, we use the well-established model system Fused in Sarcoma (FUS) to directly observe, quantify and theoretically describe fiber growth and its interplay with condensates. We report the discovery that fibers grow overwhelmingly in the dilute phase surrounding the condensates while the condensates concurrently evolve to a glassy arrested solid. The resulting protein fibers and glassy condensates are both distinct solid-like phases that coexist but do not directly interconvert. Taken together, these findings reveal that there are two competitive aging pathways in FUS condensation that are linked through phase separation kinetics.

biophysics↗

A Minimally Perturbative DARPin Probe for Quantitative Fluorescence Imaging of the Human TCR-CD3 Complex

Fluorescence microscopy is a powerful tool for dissecting the molecular mechanisms of T-cell antigen recognition in living cells, but its quantitative insight critically depends on non-perturbative, high-quality probes. Here, we repurpose a small (~15 kDa) CD3epsilon-binding DARPin (designed ankyrin repeat proteins) to a fluorescent label for T-cell receptor (TCR)/CD3 complexes on primary human CD8+ T-cells, with the aim of generating a powerful tool for quantitative analysis, single-molecule tracking, and advanced imaging of TCR dynamics. We show that the DARPin binds CD3{varepsilon} with high affinity and selectivity and using single molecule tracking and brightness analysis, we characterize the TCR-CD3 diffusion behavior and show that the DARPin binds to both CD3epsilon; subunits. Importantly, labeling preserves antigen sensitivity: on supported lipid bilayers presenting cognate pMHC, T-cells remain responsive, assemble synapses, form TCR microclusters, and initiate signaling similar to unlabeled controls. We further demonstrate compatibility with lattice light-sheet microscopy for volumetric imaging of T-cell - APC interactions in living cells. Together, these results establish DARPins as versatile, minimally perturbative probes for high resolution, quantitative studies of T cell synapse organization and signaling.

biophysics↗