Research

My research at the University of Chicago mostly consists in analyzing biological problems from the point of view of theoretical soft matter physics and statistical mechanics. I am particularly interested in making robust statements concerning these complicated systems by exploiting simple symmetry considerations, as opposed to detailed models with behaviors strongly dependent on a large number of adjustable parameters. For each topic summarized below collaborators are indicated, with experimentalists' names in italics.

A summary of my work during my Ph.D. in Institut Curie can be found here.

Contractility of non-sarcomeric actomyosin bundles

Collaborators: Todd Thoresen, Margaret Gardel, Aaron Dinner
Many moving or force-generating biological systems are based on the contractile behavior of filamentous actin (F-actin) combined with the molecular motor myosin. While the contraction of the highly organized sarcomeres found in striated muscle is well characterized, there is a lack of understanding of the contraction of the many structures devoid of this organization. Using symmetry arguments, we show that in the absence of sarcomeric organization, large bundles of rigid filaments cannot display overall contractility. This statement is valid irrespective of the complexity of the bundles and of the caracteristics of their motors. However, non-sarcomeric bundles comprised of heterogeneous molecular molecular motors powerful enough to strongly deform F-actin do lead to an overall contractile behavior. Experimental evidence indicates that these effects underly the contractility of reconstituted actomyosin bundles studied in the Gardel lab at the university of Chicago. They may also play an important role in in vivo structures lacking sarcomeric organization such as smooth muscle, graded polarity bundles, the cell cortex, the contractile ring, contractile lamellar networks etc.

Image legend:
Illustration of actomyosin contractility in the presence (top) and absence (bottom) of sarcomeric organization. Molecular motors tend to slide towards the barbed ends of the actin filaments they are connected to. In sarcomeres (top), actin filaments are organized such that this tendency results in contractile behavior. In bundles lacking this organization (bottom), the alternation of slow and fast motors induces both extensile and contractile stresses. Through the nonlinear elastic behavior of F-actin (e.g., buckling of the filaments under compression), the former are suppressed, while the latter are allowed to deform the bundle, yielding overall contractile behavior.

Publications:
Reconstitution of Contractile Actomyosin Bundles, Biophys. J. 2011
Requirements for contractility in disordered cytoskeletal bundles, New J. Phys. 2012
Contractile units in disordered actomyosin bundles arise from F-actin buckling, arXiv 2012
EM pictures of dynamin

Fiber formation by irregular aggregating objects 

Collaborator: Efraim Efrati, Tom Witten
Amyloid fibers Protein fiber formation is involved in many diseases including Alzheimer's, sickle cell anemia and type II diabetes. Although this behavior has been attributed to the specific physico-chemical characteristics of proteins, we propose that this behavior can be expected from a broad class of aggregating objects. Indeed, while simple objects such as spherical colloids tend to aggregate into three-dimensional crystals, such a regular arrangement may not be compatible with particles having a more rugged geometry. We thus propose that under certain conditions, fiber formation could be a generic characteristic of attractive irregular objects with short-range interactions.

Image legend:
Transmission electron microscopy image of a fibrilar aggregate of amyloidogenic proteins. [Dobson 2006]

Bundling and entanglement in growing cross-linked actin networks

Collaborators: Tobias Falzone, Margaret Gardel, David Kovar
F-actin is a central component of the cytoskeleton, a network of filamentous proteins that confers the cell many of its mechanical properties. Depending on its location within the cell, F-actin forms a variety of structures ranging from highly entangled networks to straight bundles of well-aligned filaments. In collaboration with the Gardel and Kovar labs at the University of Chicago, we study the competition between entanglement and alignment in in vitro F-actin networks in the presence of actin polymerization and cross-linking proteins. Due to the long time scales involved in the rearragement of the actin gel, out-of equilibrium effects dominate its morphology.

Image legend:
Molecular dynamics simulations of a network comprised of F-actin (blue) and cross-linkers (red) showing both bundled and entangled regions. [Nguyen et al. 2009]

Forthcoming publication:
"Assembly Kinetics Determine the Architecture of α‐actinin Crosslinked F‐actin Networks"
Cross-linked F-actin network

Polymerization of and chemoattraction by MIP-1

Collaborators: Min Ren, Qing Guo, Wei-Jen Tang, Aaron Dinner
MIP-1 concentration profiles
The macrophage inflamatory protein-1 (MIP-1) is a chemoattracting protein crucial for targetting the immune response against infection and inflammation. Crystallographic data from the Tang lab at the University of Chicago show that MIP-1 dimers polymerize into long helical polymers. We provide a thermodynamic analysis of the polymer size distribution and use it to analyze MIP-1 X-ray scattering data. A structural study moreover suggests that polymerization protects MIP-1 from degradation. Using a reaction-diffusion model, we study the implications of this phenomenon for MIP-1 signaling.

Image legend:
Spatial profiles of MIP-1 concentration away from an inflammation site. If only MIP-1 monomers are present (M), the MIP-1 concentration falls exponentially over a short distance. This behavior is realistic for weak inflammations (small MIP-1 concentrations). If MIP-1 dimerization is allowed (M+D), the range of the chemoattractant is increased. If dimerization and subsequent polymerization of the dimers are taken into account (M+D+P), its range is even larger - this is relevant for severe inflammations involving high MIP-1 concentrations. In that case macrophages are recruited from a large volume, allowing a strong response to the infection. Moreover, the concentration gradient of the chemoattractant flattens out near the inflammation site, thus allowing the macrophages to spread out in the vicinity of the infection and prevent its propagation.

Publication:
Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme, EMBO J. 2010


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