Protein Conformation; Thermodynamics; Protein Folding; Cell Shape
Yale Combined Program in the Biological and Biomedical Sciences (BBS): Biochemistry, Biophysics and Structural Biology: Protein Folding, Dynamics and Degradation
My research in biological physics employs both theoretical and computational approaches, including statistical mechanics descriptions and coarse-grained and atomistic molecular dynamics simulations, to study important biological problems ranging from determining the mechanical properties of skin cancer cells to understanding protein misfolding and aggregation. A key feature of my work is that it involves close collaborations with experimental biologists and students from varied backgrounds (e.g. Engineering, Physics, Biochemistry, and Computational Biology) and multi-disciplinary training.
Extensive Research Description
My research effort in biological physics employs both theoretical and computational approaches, including statistical mechanics descriptions
and coarse-grained and atomistic molecular dynamics simulations, to study
important biological problems ranging from determining the
mechanical properties of skin cancer cells to understanding protein
misfolding and aggregation. All of the projects described below involve close collaborations with experimental biologists.
1. Smart, designer, protein-based nanogels: We design, create, and characterize new classes of stimuli-responsive biomaterials. A distinguishing feature of these materials is the incorporation of tetratricopeptide (TPR) modules of defined structure and stability and cross-linkers between TPRs to create a scaffold with structural integrity. Cross-linking in these novel materials is governed by specific TPR-peptide interactions. We are able to design and manipulate the microscopic components and their interactions with unprecedented control in these materials. We combine experimental measurements with coarse-grained computer simulations to understand and define the macroscopic consequences of particular designs. This coordinated process will lead to a new generation of active biomaterials with unprecedented, highly-specific molecular recognition capabilities and response to external stimuli. Collaborators on this project include Profs. Eric Dufresne (Mechanical Engineering, Chemical Engineering, Cell Biology, and Physics) and Lynne Regan (Molecular Biophysics & Biochemistry, Chemistry).
2. Understanding the structural and mechanical properties of epithelial cells:
The goal of this project is to first determine the structural properties (cell size and shape) and mechanical constraints (intercellular forces and packing geometry) of normal epithelial tissue and then identify how these properties evolve during cancer progression and wound healing. This work is based on the hypothesis that tumor
formation and cell motion during wound healing can be directly linked to changes in the mechanical properties of the tissue. We will address three fundamental open questions in this project: 1) Does the structure, packing geometry, and force-bearing properties of cells and tissues change during tumorigenesis? 2) Is there a feedback effect, in which these changes promote the progression of tumorigenesis? and 3) To what extent can wound healing be modeled by mechanical response without biochemical signaling? Collaborators on this project include Profs. Eric Dufresne (Mechanical Engineering & Materials Science, Chemical Engineering, Cell Biology) and Valerie Horsley (MCDB).
4. Nanoscale approaches to screening small molecule inhibitors of toxic amyloid species in neurodegenerative disease: Single molecule measurements are uniquely capable of characterizing the dynamic set of molecular species that are populated during amyloid aggregation. We will combine experimental single molecule fluorescence methods with computer simulations to develop a novel approach to determine how soluble amyloid species interact with small organic molecules. We will develop our methods using the Parkinson's Disease associated protein, alpha-synuclein, and the Alzheimer's Disease associated protein, tau. Using small molecules that have been identified for their ability to perturb aggregation of these proteins, we will study their effects on protein conformational dynamics and oligomerization process. We will specifically address two questions: (1) how do small molecules affect monomer structures and their dynamics and (2) what is the effect of small molecules on oligomerization. The results of these investigations will provide an ultrasensitive, robust assay for screening small molecules that perturb soluble pre-fibrillar amyloid species. Thus, if successful,
our proposed research will lead to a transformative change in the way small-molecule drugs are screened, the ultimate outcome of which is the development of drugs to treat or prevent Parkinson's, Alzheimer's, and other amyloid diseases. This work will be performed in collaboration with Prof. Elizabeth Rhoades (MB&B, Physics).
- Prediction of the Binding Affinity for Hydrophobic Protein-Protein Interactions
- Modeling the Conformational Dynamics of the Intrinsically Disordered Proteins alpha-synuclein and tau.
- Modeling the Collective Motion of Epithelial Cells in Response to Wounding
- Modeling Changes in the Structural and Mechanical Properties of Epithelial Cells during Tumor Formation
- G. Lois, J. Blawzdziewicz, and C. S. O'Hern, "Reliable Protein Folding on Complex Energy Landscapes: The Free Energy Reaction Path", Biophys. J. 95 (2008) 2692.
- A. L. Cortajarena, G. Lois, E. Sherman, C. S. O'Hern, L. Regan, and G. Haran, "Non-random-coil behavior as a consequence of extensive PPII structure in the denatured state", J. Mol. Biol. 382 (2008) 203.
- G. Lois, J. Blawzdziewicz, and C. S. O'Hern, "Percolation Model for Slow Dynamics in Glass-Forming Materials", Phys. Rev. Lett. 102 (2009) 015702.
- M. Mailman, C. F. Schreck, B. Chakraborty, and C. S. O'Hern, "Jamming in Systems Composed of Frictionless Ellipse-Shaped Particles", Phys. Rev. Lett. 102 (2009) 255501
- G. Lois, J. Blawzdziewicz, and C. S. O'Hern, "Protein folding on rugged energy landscapes: Conformational diffusion on fractal networks", Phys. Rev. E 81 (2010) 051907.
- R. Hoy and C. S. O'Hern, "Minimal energy packings and collapse of sticky tangent hard-sphere polymers," Phys. Rev. Lett. 105 (2010) 068001.