Molecules and Cells

Over the last few decades, structural biologists have delivered a treasure-trove of data on the shapes and sizes of large biomacromolecules and their assemblies. When this information is combined with aspects of their kinetics, we can begin to ask questions about how structure impacts function dynamically at both the level of the individual molecule and in polymeric filaments, networks and larger assemblies.

We are particularly interested in the statistical and continuum mechanics of macromolecular assemblies such as disordered cytoskeletal-like networks of actin and crosslinkers, ordered assemblies such as microtubules, actin bundles, DNA-loops etc. in the context of questions such as the linear and nonlinear rheology of these “living” materials”, the kinetics of growth and shrinkage, and the mechanochemistry of active biological engines driven by growth, shrinkage and spring-like behavior. Recently, we have also become interested in how we might control the formation and dissolution of  protein and liquid aggregates in the context of amyloid diseases, liquid-liquid phase separation, bringing in ideas from deterministic, stochastic, feedback and feedforward control theory to study these questions. At the cellular level, we have explored the statistical and continuum dynamics of the immunological synapse patterns, scaling theories for cell spreading, the biophysics of cell blebbing, dynamics of cellular sensing, decision-making and movement, and the large scale motion of cells in multi-cellular tissues.

Early work in this area focused on coarse-grained models of DNA mechanics, with the continuum and statistical mechanics of the Lac operon loop and complex. Later work considered the mechanics and kinetics of the acrosomal reaction in the horseshoe crab sperm, a remarkable example of an active cross-linked assembly of actin that changes conformation in a few seconds on being exposed to calcium ions (in the vicinity of an egg). This led to experimental studies of the kinetics and force production, and of the dynamical process modeled as a structural phase transition.

Later, we started to work on the continuum and statistical mechanics of cytoskeletal actin networks to understand the scaling of their rheological properties, the kinetics of dynamical instabilities in growing and shrinking microtubules, the growth-induced force production of actin networks, and gradually moved towards understanding the mechanics of cells. To characterize the mechanical behavior of the cytoplasm, inspired by experiments on blebbing, we suggested that one should think of the cytoplasm as a soft, active fluid-filled sponge, now amply borne out by multiple experiments. This allowed us to explain the formation and motion of circus blebs and a primitive mode of motility. We also provided a simple approach to cell spreading using an analogy to an active drop, with scaling laws corroborated by experiments on a range of different cell types.

Related Publications

Mechanics and kinetics of dynamic instability. T.C.T. Michaels, S. Feng, H. Liang, and L Mahadevan, eLife, 9:e54077, 2020. [DOI] [View PDF] [Download PDF]
Mechanical basis for fibrillar bundle morphology. T. Michaels, E. Memet, and L. Mahadevan, Soft Matter , 16, 9306-18, 2020. [ONLINE ARTICLE] [DOI] [View PDF] [Download PDF]
Motility driven by macromolecular springs and ratchets, Mahadevan, L. and P. Matsudaira,  Science , 288, 95-99, 2000. [View PDF] [Download PDF]
Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcements C. Brangwynne, F. Mackintosh, S. Kumar, N. Geisse, J. Talbot, L. Mahadevan, K. Parker, D. Ingber and D. Weitz,  Journal of Cell Biology  , 173, 733, 2006. [View PDF] [Download PDF]
A quantitative analysis of contractility in active cytoskeletal protein networks P. Bendix, G. Koenderink, D. Cuvelier, Z. Dogic, B. Koeleman, W. Brieher, C. Field, L. Mahadevan and D. Weitz,  Biophysical Journal,  94, 3126, 2008. [View PDF] [Download PDF]
Elastic model of a DNA loop in the lac operon,  Balaeff, A., L. Mahadevan, and K. Schulten,  Physical Review Letters , 83, 4900-03, 1999. [View PDF] [Download PDF]
Modeling DNA loops using the theory of elasticity A. Balaeff, L. Mahadevan and K. Schulten,  Physical Review E,  73, 031919, 2006. [View PDF] [Download PDF]
Multiscale methods for modeling protein-DNA complexes, Villa, E. , Balaeff, A., L. Mahadevan and K. Schulten,  SIAM Multiscale Modeling and Simulation , 2, 527-553 (2004). [View PDF] [Download PDF]
Force of an actin spring J.H. Shin, B.K. Tam, R.R. Brau, M.J. Lang, L. Mahadevan, and Paul Matsudaira,  Biophysical Journal , 92, 3729, 2007. [View PDF] [Download PDF]
Elastic behavior of cross-linked and bundled actin networks,  Gardel, M., J. Shin, F. Mackintosh, L. Mahadevan, P. Matsudaira and D. Weitz,  Science,  304, 1301-5, 2004. [View PDF] [Download PDF]
Relating microstructure to rheology of a bundled and cross-linked F-actin network in-vitro Shin, J., M. Gardel, L. Mahadevan, P. Matsudaira and D. Weitz,  Proceedings of the National Academy of Sciences (USA) , 101(26), 9636-41 (2004). [View PDF] [Download PDF]
Actin network growth under load O. Campàs, L. Mahadevan, and J-F. Joanny,  Biophysical Journal , 102, 1049-1058, 2012. [View PDF] [Download PDF]
Calcium regulation of an actin spring B. Tam, J. Shin, E. Pfeiffer, P. Matsudaira and L. Mahadevan,  Biophysical Journal , 97, 1125, 2009. [View PDF] [Download PDF]
Power-limited contraction dynamics of Vorticella convallaria: an ultrafast biological spring A. Upadhyaya, M. Baraban, J. Wong, P. Matsudaira, A. van Oudenaarden and L. Mahadevan,  Biophysical Journal , 94, 265, 2008. [View PDF] [Download PDF]
Structural dynamics of an actin spring L. Mahadevan, C. Riera and J. Shin  Biophysical Journal , 100, 839-44, 2011. [View PDF] [Download PDF]
Stored elastic energy powers the 60-micron extension of the Limulus polyphemus sperm actin bundle, Shin, J., L. Mahadevan, G. Waller, K. Langsmo and P. Matsudaira,  Journal of Cell Biology , 162(7), 1183-88, 2003. [View PDF] [Download PDF]
The universal dynamics of cell spreading D. Cuvelier, M. Thery, Y-S. Chu, S. Dufour, J-P. Thiery, M. Bornens, P. Nassoy, and L. Mahadevan,  Current Biology  , 17, 694, 2007. [View PDF] [Download PDF]
Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells H.V. Prentice-Mott, Y. Meroz, A. Carlson, M.A. Levine, M.W. Davidson, D. Irimia, G.T. Charras, L. Mahadevan, and J.V. Shah,  Proceedings of the National Academy of Sciences  (USA) 113, 1267-72, 2016. [View PDF] [Download PDF]
Life and times of a cellular bleb G. Charras, M. Coughlin, T. Mitchison and L. Mahadevan,  Biophysical Journal,  94, 1836, 2008. [View PDF] [Download PDF]
Non-equilibration of hydrostatic pressure in blebbing cells, G. Charras, J. Yarrow, M. Horton, L. Mahadevan and T. Mitchison,  Nature , 435, 365-69. 2005. [View PDF] [Download PDF]
Dynamics of growth and form in prebiotic vesicles
T. Herrero-Ruiz, T. Fai, L. Mahadevan, Physical Review Letters 123, 038102, 2019. [DOI] [View PDF] [Download PDF]
Elastohydrodynamics and kinetics of protein patterning in the immunological synapse
A. Carlson, L. Mahadevan,  PLoS Comput Biol  11(12): e1004481, 2015.  [View PDF] [Download PDF]
Bacillus spores as building blocks for stimuli-responsive materials and nanogenerators X. Chen, L. Mahadevan, A. Driks and O. Sahin,  Nature Nanotechnology , 9, 137-141, 2014. [View PDF] [Download PDF]
Physical basis for the adaptive flexibility of bacillus spore coats O. Sahin, E-H Yong, A. Driks and L. Mahadevan,  Journal of the Royal Society - Interface,  9, 3156-3160, 2012. [View PDF] [Download PDF]