Hinczewski Lab


Theoretical Biophysics Research Group

                

Research overview


Our group is interested in the mechanical dimension of cellular biology: the forces and deformations that propagate through the cell's densely packed interior during transport, signaling, growth, and division. Thanks to advances in single-molecule experimental probes, we know that cellular mechanics are a critical factor in a variety of behaviors such as neural plasticity and cancer metastasis. We seek to complete the picture through theoretical models that connect the long-time, large-scale dynamics of cellular processes—accessible to experiment—with microscopic descriptions that capture the essential physics and chemistry driving the system. Click on the topics below for more information on current areas of research:
  • Motor Proteins

    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?

    Read more:
    M. Hinczewski, R. Tehver, and D. Thirumalai, "Design principles governing the motility of myosin V", Proc. Natl. Acad. Sci. 110, E4059 (2013). 
    Research highlight: A. Klopper, "Walk the line", Nature Physics 9, 692 (2013).
  • Cell Adhesion

    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 exploit this data to understand 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?

    Read more:
    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).  
  • Signaling

    Receptors in the cell surface 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.

    Read more:
    D. Hathcock, J. Sheehy, C. Weisenberger, E. Ilker, M. Hinczewski, "Noise Filtering and Prediction in Biological Signaling Networks", IEEE Trans. Mol. Biol. Multi-Scale Commun. 2, 16 (2016) (2016). 
    M. Hinczewski and D. Thirumalai, "Noise control in gene regulatory networks with negative feedback", J. Phys. Chem. B 120, 6166 (2016). 
    M. Hinczewski and D. Thirumalai, "Cellular signaling networks function as generalized Wiener-Kolmogorov filters to suppress noise", Phys. Rev. X 4, 041017 (2014). 
  • Force Spectroscopy

    The precision and stability of optical tweezers have given us tantalizing glimpses of individual biomolecules folding and unfolding under force. However the theory relating what is observed in the lab—the displacements of optically trapped beads—and the actual conformational changes of the molecule, is still incomplete. We are working on methods to allow experimentalists to reliably extract intrinsic molecular properties like free energy landscapes and folding dynamics.

    Read more:
    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).  
    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).  
    M. Hinczewski, Y. von Hansen, and R.R. Netz, "Deconvolution of dynamic mechanical networks", Proc. Natl. Acad. Sci. U.S.A. 107, 21493 (2010).  
  • Biopolymer Dynamics

    Polymers are a central motif in cellular systems, and we are interested in applying theories of polymer dynamics to describe biological processes: from the fluctuations of DNA chains and their role in the association of DNA-binding proteins, to how semiflexible polymers like cytoskeletal filaments respond to tension.

    Read more:
    M. Hinczewski and R.R. Netz, "Anisotropic Hydrodynamic Mean-Field Theory for Semiflexible Polymer Dynamics under Tension", Macromolecules 44, 6972 (2011).  
    Y. von Hansen, R.R. Netz, and M. Hinczewski, "DNA-protein binding rates: Bending fluctuation and hydrodynamic coupling effects", J. Chem. Phys. 132, 135103 (2010).  
    M. Hinczewski and R.R. Netz, "Global cross-over dynamics of single semiflexible polymers", EPL 88, 18001 (2009).  

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