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.
T. Herrero-Ruiz, T. Fai, L. Mahadevan, Physical Review Letters 123, 038102, 2019. [DOI] [View PDF] [Download PDF]
A. Carlson, L. Mahadevan, PLoS Comput Biol 11(12): e1004481, 2015. [View PDF] [Download PDF]