Sam Walcott joined the Department in 2011 after earning a Ph.D. in theoretical and applied mechanics from Cornell University and doing postdocs in experimental and theoretical biophysics at the University of Vermont and Johns Hopkins. His research develops models that predict large-scale biological phenomena from single molecule mechanics. One important focus of his work is muscle mechanics.
The muscle contractions that underlie the heartbeat and other physiological processes involve ratchet-like interactions between myosin molecules and actin molecules. When myosin binds to the actin filament, it undergoes a conformational change that moves the filament. As it unbinds, this conformational change is reversed, making the myosin ready to rebind and ratchet again. When this cyclic process occurs at many molecules within a muscle cell, it causes that cell to contract.
Single myosin molecules can be isolated and their interactions with single actin filaments observed. In this way the rates of their reactions, the size of myosin’s conformational change, and the mechanical properties of myosin and actin have all been measured. Recent experiments have shown that myosin’s mechanics and chemistry are coupled through a chemical reaction whose rate depends on force. If myosin experiences a force resisting its conformation change, the reaction occurs more slowly than if myosin experiences an assistive force.
While these experiments define the actions of single molecules, groups of molecules working together behave differently. Sam’s research addresses this problem. He uses mathematics to relate the behavior of single proteins to their functions in groups. In collaboration with experimentalists, he develops and tests models that make predictions at successively larger size scales.
In a recent paper, for example, he incorporated measurements of single myosin molecules into computer simulations to predict their collective, group behavior. Interestingly, these simulations and the corresponding experiments both find that myosin molecules working together move actin faster than one myosin working alone. The mathematical analysis shows why: Myosin molecules working together apply forces on each other. These increase their detachment rates from actin, which in turn increases the muscle contraction speed. This work shows how problems affecting myosin molecule interactions can lead to disease, insight single molecule measurements cannot provide.
This picture becomes more complex when one considers the other proteins that regulate myosin binding. These proteins make the binding of myosin to actin cooperative; one binding event facilitates the binding of other nearby myosin molecules. If two nearby myosins bind to actin, they accelerate the binding of additional myosins more than they would if they were far apart. Recently, Sam has derived the first differential equation model of myosin binding that includes cooperative myosin groups and shown it to accurately and efficiently reproduce experimental measurements.
Sam’s long term goal is to develop a series of mathematical models describing muscle contraction that extend from single molecules to the complete organ. This work has the potential to transform our understanding of muscle contraction. His present work is laying the groundwork for a full, quantitative understanding of heart muscle contractions in particular. His research will illuminate both normal heart function and the molecular bases of several cardiac diseases and has the potential to lead to new medical treatments.