Corey O'Hern, PhD

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).

1. Prediction of the Binding Affinity for Hydrophobic Protein-Protein Interactions
2. Modeling the Conformational Dynamics of the Intrinsically Disordered Proteins alpha-synuclein and tau.
3. Modeling the Collective Motion of Epithelial Cells in Response to Wounding
4. Modeling Changes in the Structural and Mechanical Properties of Epithelial Cells during Tumor Formation