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.
Full List of PubMed Publications
- Noble DB, Mochrie SG, O'Hern CS, Pollard TD, Regan L: Promoting convergence: The integrated graduate program in physical and engineering biology at Yale University, a new model for graduate education. Biochem Mol Biol Educ. 2016 Nov 12; 2016 Jun 13. PMID: 27292366
- Wang K, Langevin S, O'Hern CS, Shattuck MD, Ogle S, Forero A, Morrison J, Slayden R, Katze MG, Kirby M: Anomaly Detection in Host Signaling Pathways for the Early Prognosis of Acute Infection. PLoS One. 2016 Aug 17; 2016 Aug 17. PMID: 27532264
- Virrueta A, O'Hern CS, Regan L: Understanding the physical basis for the side-chain conformational preferences of methionine. Proteins. 2016 Jul; 2016 Apr 6. PMID: 26917446
- Gaines JC, Smith WW, Regan L, O'Hern CS: Random close packing in protein cores. Phys Rev E. 2016 Mar; 2016 Mar 28. PMID: 27078398
- Bertrand T, Behringer RP, Chakraborty B, O'Hern CS, Shattuck MD: Protocol dependence of the jamming transition. Phys Rev E. 2016 Jan; 2016 Jan 11. PMID: 26871137
- Rokhlenko Y, Gopinadhan M, Osuji CO, Zhang K, O'Hern CS, Larson SR, Gopalan P, Majewski PW, Yager KG: Magnetic Alignment of Block Copolymer Microdomains by Intrinsic Chain Anisotropy. Phys Rev Lett. 2015 Dec 18; 2015 Dec 18. PMID: 26722950
- Zhang K, Fan M, Liu Y, Schroers J, Shattuck MD, O'Hern CS: Beyond packing of hard spheres: The effects of core softness, non-additivity, intermediate-range repulsion, and many-body interactions on the glass-forming ability of bulk metallic glasses. J Chem Phys. 2015 Nov 14. PMID: 26567672
- Clark AH, Shattuck MD, Ouellette NT, O'Hern CS: Onset and cessation of motion in hydrodynamically sheared granular beds. Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Oct; 2015 Oct 16. PMID: 26565230
- Mai M, Wang K, Huber G, Kirby M, Shattuck MD, O'Hern CS: Outcome Prediction in Mathematical Models of Immune Response to Infection. PLoS One. 2015 Aug 19; 2015 Aug 19. PMID: 26287609
- Zhang K, Dice B, Liu Y, Schroers J, Shattuck MD, O'Hern CS: On the origin of multi-component bulk metallic glasses: Atomic size mismatches and de-mixing. J Chem Phys. 2015 Aug 7. PMID: 26254655
- Caballero D, Smith WW, O'Hern CS, Regan L: Equilibrium transitions between side-chain conformations in leucine and isoleucine. Proteins. 2015 Aug. PMID: 26018846
- Regan L, Caballero D, Hinrichsen MR, Virrueta A, Williams DM, O'Hern CS: Protein design: Past, present, and future. Biopolymers. 2015 Jul. PMID: 25784145
- Zhang K, Liu Y, Schroers J, Shattuck MD, O'Hern CS: The glass-forming ability of model metal-metalloid alloys. J Chem Phys. 2015 Mar 14. PMID: 25770548
- Wang M, Zhang K, Li Z, Liu Y, Schroers J, Shattuck MD, O'Hern CS: Asymmetric crystallization during cooling and heating in model glass-forming systems. Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Mar; 2015 Mar 17. PMID: 25871112
- Shao Z, Singer JP, Liu Y, Liu Z, Li H, Gopinadhan M, O'Hern CS, Schroers J, Osuji CO: Shear-accelerated crystallization in a supercooled atomic liquid. Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Feb; 2015 Feb 18. PMID: 25768445
- Smith WW, Ho PY, O'Hern CS: Calibrated Langevin-dynamics simulations of intrinsically disordered proteins. Phys Rev E Stat Nonlin Soft Matter Phys. 2014 Oct; 2014 Oct 13. PMID: 25375525
- Zhou AQ, O'Hern CS, Regan L: Predicting the side-chain dihedral angle distributions of nonpolar, aromatic, and polar amino acids using hard sphere models. Proteins. 2014 Oct; 2014 Aug 11. PMID: 24912976
- Shen T, Papanikolaou S, O'Hern CS, Shattuck MD: Statistics of frictional families. Phys Rev Lett. 2014 Sep 19; 2014 Sep 15. PMID: 25279647
- Zhang K, Smith WW, Wang M, Liu Y, Schroers J, Shattuck MD, O'Hern CS: Connection between the packing efficiency of binary hard spheres and the glass-forming ability of bulk metallic glasses. Phys Rev E Stat Nonlin Soft Matter Phys. 2014 Sep; 2014 Sep 29. PMID: 25314450
- Caballero D, Määttä J, Zhou AQ, Sammalkorpi M, O'Hern CS, Regan L: Intrinsic α-helical and β-sheet conformational preferences: a computational case study of alanine. Protein Sci. 2014 Jul; 2014 May 9. PMID: 24753338
- Bertrand T, Schreck CF, O'Hern CS, Shattuck MD: Hypocoordinated solids in particulate media. Phys Rev E Stat Nonlin Soft Matter Phys. 2014 Jun; 2014 Jun 12. PMID: 25019766
- Parry BR, Surovtsev IV, Cabeen MT, O'Hern CS, Dufresne ER, Jacobs-Wagner C: The bacterial cytoplasm has glass-like properties and is fluidized by metabolic activity. Cell. 2014 Jan 16; 2013 Dec 19. PMID: 24361104
- Wang K, Bhandari V, Chepustanova S, Huber G, O'Hara S, O'Hern CS, Shattuck MD, Kirby M: Which biomarkers reveal neonatal sepsis? PLoS One. 2013 Dec 18; 2013 Dec 18. PMID: 24367543
- Zhou AQ, Caballero D, O'Hern CS, Regan L: New insights into the interdependence between amino acid stereochemistry and protein structure. Biophys J. 2013 Nov 19. PMID: 24268152
- Schreck CF, Hoy RS, Shattuck MD, O'Hern CS: Particle-scale reversibility in athermal particulate media below jamming. Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Nov; 2013 Nov 25. PMID: 24329257
- Geerts N, Schreck CF, Beales PA, Shigematsu H, O'Hern CS, Vanderlick TK: Using DNA-driven assembled phospholipid nanodiscs as a scaffold for gold nanoparticle patterning. Langmuir. 2013 Oct 22; 2013 Oct 10. PMID: 24073728
- Zhang K, Wang M, Papanikolaou S, Liu Y, Schroers J, Shattuck MD, O'Hern CS: Computational studies of the glass-forming ability of model bulk metallic glasses. J Chem Phys. 2013 Sep 28. PMID: 24089782
- Papanikolaou S, O'Hern CS, Shattuck MD: Isostaticity at frictional jamming. Phys Rev Lett. 2013 May 10; 2013 May 7. PMID: 23705742
- O'Hern CS, Shattuck MD: Granular materials: highly evolved grains. Nat Mater. 2013 Apr. PMID: 23511577
- Nath A, Sammalkorpi M, DeWitt DC, Trexler AJ, Elbaum-Garfinkle S, O'Hern CS, Rhoades E: The conformational ensembles of α-synuclein and tau: combining single-molecule FRET and simulations. Biophys J. 2012 Nov 7. PMID: 23199922
- Smith WW, Schreck CF, Hashem N, Soltani S, Nath A, Rhoades E, O'Hern CS: Molecular simulations of the fluctuating conformational dynamics of intrinsically disordered proteins. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Oct; 2012 Oct 12. PMID: 23214618
- Shen T, Schreck C, Chakraborty B, Freed DE, O'Hern CS: Structural relaxation in dense liquids composed of anisotropic particles. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Oct; 2012 Oct 10. PMID: 23214576
- Ashwin SS, Blawzdziewicz J, O'Hern CS, Shattuck MD: Calculations of the structure of basin volumes for mechanically stable packings. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Jun; 2012 Jun 19. PMID: 23005086
- Schreck CF, Mailman M, Chakraborty B, O'Hern CS: Constraints and vibrations in static packings of ellipsoidal particles. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Jun; 2012 Jun 13. PMID: 23005084
- Zhou AQ, O'Hern CS, Regan L: The power of hard-sphere models: explaining side-chain dihedral angle distributions of Thr and Val. Biophys J. 2012 May 16; 2012 May 15. PMID: 22677388
- Hoy RS, Harwayne-Gidansky J, O'Hern CS: Structure of finite sphere packings via exact enumeration: implications for colloidal crystal nucleation. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 May; 2012 May 22. PMID: 23004757
- Shen T, O'Hern CS, Shattuck MD: Contact percolation transition in athermal particulate systems. Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Jan; 2012 Jan 27. PMID: 22400566
- Forster JD, Park JG, Mittal M, Noh H, Schreck CF, O'Hern CS, Cao H, Furst EM, Dufresne ER: Assembly of optical-scale dumbbells into dense photonic crystals. ACS Nano. 2011 Aug 23; 2011 Jul 15. PMID: 21740047
- Schreck CF, Bertrand T, O'Hern CS, Shattuck MD: Repulsive contact interactions make jammed particulate systems inherently nonharmonic. Phys Rev Lett. 2011 Aug 12; 2011 Aug 12. PMID: 21902435
- Schreck CF, O'Hern CS, Silbert LE: Tuning jammed frictionless disk packings from isostatic to hyperstatic. Phys Rev E Stat Nonlin Soft Matter Phys. 2011 Jul; 2011 Jul 27. PMID: 21867162
- Zhou AQ, O'Hern CS, Regan L: Revisiting the Ramachandran plot from a new angle. Protein Sci. 2011 Jul; 2011 May 31. PMID: 21538644
- Hoy RS, O'Hern CS: Viscoplasticity and large-scale chain relaxation in glassy-polymeric strain hardening. Phys Rev E Stat Nonlin Soft Matter Phys. 2010 Oct; 2010 Oct 13. PMID: 21230304
- Hoy RS, O'Hern CS: Minimal energy packings and collapse of sticky tangent hard-sphere polymers. Phys Rev Lett. 2010 Aug 6; 2010 Aug 5. PMID: 20868016
- Forster JD, Noh H, Liew SF, Saranathan V, Schreck CF, Yang L, Park JG, Prum RO, Mochrie SG, O'Hern CS, Cao H, Dufresne ER: Biomimetic isotropic nanostructures for structural coloration. Adv Mater. 2010 Jul 20. PMID: 20414884
- Gao GJ, Blawzdziewicz J, O'Hern CS, Shattuck M: Experimental demonstration of nonuniform frequency distributions of granular packings. Phys Rev E Stat Nonlin Soft Matter Phys. 2009 Dec; 2009 Dec 17. PMID: 20365165
- Gao GJ, Blawzdziewicz J, O'Hern CS: Geometrical families of mechanically stable granular packings. Phys Rev E Stat Nonlin Soft Matter Phys. 2009 Dec; 2009 Dec 16. PMID: 20365164
- Lois G, Blawzdziewicz J, O'Hern CS: Percolation model for slow dynamics in glass-forming materials. Phys Rev Lett. 2009 Jan 9; 2009 Jan 6. PMID: 19257212
- Cortajarena AL, Lois G, Sherman E, O'Hern CS, Regan L, Haran G: Non-random-coil behavior as a consequence of extensive PPII structure in the denatured state. J Mol Biol. 2008 Sep 26; 2008 Jul 11. PMID: 18644382
- Lois G, Blawzdziewicz J, O'Hern CS: Reliable protein folding on complex energy landscapes: the free energy reaction path. Biophys J. 2008 Sep 15; 2008 May 30. PMID: 18515400
- Lois G, Blawzdziewicz J, O'Hern CS: Jamming transition and new percolation universality classes in particulate systems with attraction. Phys Rev Lett. 2008 Jan 18; 2008 Jan 17. PMID: 18232929
- Gao GJ, Bławzdziewicz J, O'Hern CS: Frequency distribution of mechanically stable disk packings. Phys Rev E Stat Nonlin Soft Matter Phys. 2006 Dec; 2006 Dec 13. PMID: 17280059
- Xu N, O'Hern CS: Measurements of the yield stress in frictionless granular systems. Phys Rev E Stat Nonlin Soft Matter Phys. 2006 Jun; 2006 Jun 16. PMID: 16906818
- Xu N, O'Hern CS, Kondic L: Stabilization of nonlinear velocity profiles in athermal systems undergoing planar shear flow. Phys Rev E Stat Nonlin Soft Matter Phys. 2005 Oct; 2005 Oct 13. PMID: 16383382
- Xu N, Blawzdziewicz J, O'Hern CS: Random close packing revisited: ways to pack frictionless disks. Phys Rev E Stat Nonlin Soft Matter Phys. 2005 Jun; 2005 Jun 28. PMID: 16089734
- Xu N, O'Hern CS: Effective temperature in athermal systems sheared at fixed normal load. Phys Rev Lett. 2005 Feb 11; 2005 Feb 7. PMID: 15783661
- Xu N, O'Hern CS, Kondic L: Velocity profiles in repulsive athermal systems under shear. Phys Rev Lett. 2005 Jan 14; 2005 Jan 5. PMID: 15698098
- O'Hern CS, Liu AJ, Nagel SR: Effective temperatures in driven systems: static versus time-dependent relations. Phys Rev Lett. 2004 Oct 15; 2004 Oct 15. PMID: 15525004