Quantitative Biology Colloquium
Using molecular mechanics to predict large-scale biological function: applications to muscle activation and intracellular transport
Simple mechanical models at the molecular scale can help us understand complex emergent behavior at larger size scales. In this talk, I will show how this approach applies to two biological processes: (1) the activation of striated muscle, and (2) intracellular transport by molecular motors.
(1) Animals adopt movement strategies that minimize metabolic cost. Predicting metabolic cost from a given movement would therefore be useful for human/animal movement studies. Chemical energy consumption by muscles underlies metabolic cost, so it seems intuitive that recent increases in understanding of muscle contraction at the molecular scale would translate to better metabolic cost models. But, reliable models remain elusive, in part because experimental work has focused on understanding the interaction of the force-generating molecule myosin II with the structural protein actin. In muscle, this interaction is tightly regulated by another set of proteins. These regulatory proteins fundamentally change the molecular interactions by introducing local coupling between myosin II molecules. I will discuss some new methods to measure activation at the molecular scale, and will present some models that can describe activation from the single molecule to the whole muscle scale. I will then discuss how these models might lead to new, accurate metabolic cost models.
(2) Inside a cell, material must be transported large distances to specific targets. Passive diffusion is too slow and imprecise, so eukaryotic cells employ molecular motors (like myosin Va), which use chemical energy to "walk" along the 3D network of protein filaments (like actin) of the cytoskeleton. Despite a wealth of experimental and theoretical work at the single molecule level, it is unclear how molecular motors work together to navigate their cargoes through the apparent random tangle of the cytoskeleton. I will discuss a series of experiments aimed at unraveling this process, and a mathematical model that makes sense of the experimental results. The central result of this work is that the local geometry of an actin intersection dictates if and how long teams of myosin Va motors become stationary. Cells control the geometry of actin intersections via a series of proteins (e.g. Arp2/3, filamin, fascin, etc.), suggesting that regulating the expression these proteins regulates intracellular transport.