Theoretical biophysics and soft matter: motor proteins, single-molecule force spectroscopy, biopolymers, cell adhesion, signaling networks
Random fluctuations pervade cellular biology, from the level of individual biochemical reactions to the intricate machinery responsible for transport and signaling. And yet despite the noise at all scales, collective order emerges: a bewildering hierarchy of interconnected processes, carefully arranged throughout the volume of the cell. To understand this organization, we need to come to grips not only with the biochemistry involved, but the cell’s material aspects: the jostling of the multitudes of proteins and nucleic acids within its crowded interior, the push and pull of the external environment. The resulting mechanical forces and deformations play a major role in cellular behaviors, from the plasticity of neurons to the spread of tumors. Our group tries to make sense of all this through the lens of statistical physics, which provides a set of powerful tools for exploring complex, stochastic systems. We study a broad range of cellular functions, with a common goal of connecting the long-time, large-scale dynamics, accessible to experimental probes, with a microscopic description that captures the essential physics and chemistry underlying the phenomenon. Among the topics we are interested in:
- Molecular motors: one way in which cells maintain spatial organization is through motor proteins that bind cargo and move it along networks of cytoskeletal filaments. These proteins—myosins, kinesins, dynein among others—exist in a host of different forms, and we are interested in the common structural design principles behind their dynamics. What explains a motor’s transport efficiency, its perseverance under load, its distribution of step sizes and binding locations? By altering elements of their structure, can we bioengineer motors toward specific biomedical applications?
- Cell adhesion proteins: in order to latch onto their surroundings, cells exploit an array of interactions between receptor proteins embedded in their surfaces and external binding partners. These adhesion bonds are often subject to significant mechanical forces, for example a white blood cell halting at a site of inflammation in a rapidly flowing blood vessel. Single molecule experiments have measured the force response of many adhesion proteins, and we would like to complete the picture by understanding the conformational changes in protein structure that determine the bond kinetics. At a larger scale, to what extent is a bond’s survival time over a range of forces optimized for the physiological conditions in which the interaction is likely to occur?
- Cellular signaling: receptors in the cell surface also have a communications role, by binding to signaling molecules like hormones and initiating cascades of chemical reactions in the cell interior. The ability of the cell to accurately process and respond to these environmental cues is limited by the noise introduced in the reaction networks that propagate and amplify the signal. We are interested in the ways cells have evolved to cope with this noise, particularly the striking parallels between biological noise filtering mechanisms and those in human-designed communications systems. Ideas from the latter, like Wiener-Kolmogorov optimal filter theory, turn out to have direct implications for biochemical signaling circuits.
M. Hinczewski and D. Thirumalai, “Cellular signaling networks function as generalized Wiener-Kolmogorov filters to suppress noise” Phys. Rev. X in press (2014).
B. Ramm, J. Stigler, M. Hinczewski, D. Thirumalai, H. Herrmann, G. Woehlke, and M. Rief, “Sequence-resolved free energy profiles of stress-bearing vimentin intermediate filaments” Proc. Natl. Acad. Sci. 111, 11359 (2014).
S. Chakrabarti, M. Hinczewski, and D. Thirumalai, “Plasticity of hydrogen bond networks regulates mechanochemistry of cell adhesion complexes” Proc. Natl. Acad. Sci. 111, 9048 (2014).
C. Hyeon, M. Hinczewski, and D. Thirumalai, “Evidence of disorder in biological molecules from single molecule pulling experiments” Phys. Rev. Lett. 112, 138101 (2014).
M. Hinczewski, R. Tehver, and D. Thirumalai, “Design principles governing the motility of myosin V” Proc. Natl. Acad. Sci. 110, E4059 (2013).
M. Hinczewski, J.C.M. Gebhardt, M. Rief, and D. Thirumalai, “From mechanical folding trajectories to intrinsic energy landscapes of biopolymers” Proc. Natl. Acad. Sci. 110, 4500 (2013).
Rockefeller Building 105A
B.S., Yale University (1999)
Ph.D., Massachusetts Institute of Technology (2005)