Protein folding, misfolding, and aggregation

Most proteins fold into specific three-dimensional structures, which determine their functions. The folding process can be described by the free energy landscape as in a first order phase transition. The native state features the lowest free energy and correspond to the most stable and most populated species in physiological conditions. However, due to either environmental changes or mutations, the native states are destabilized. The intermediate(s) and unfolded states are promoted, where protein exposes their hydrophobic core and un-satisfied hydrogen bond donors and acceptors. These non-native species are sticky in nature and tends to aggregate under high concentrations. The aggregation is a nucleation process, and the final aggregates can adopt a fibrillar shape depending on the structural and dynamical properties of the aggregation precursor species. For a long time, the fibrillar aggregation, a.k.a. amyloid fibrils, has been thought to cause a long list of amyloid diseases, including Alzheimers’, Parkinson’s, Lou Gehrig’s diseases. Recent experiments have suggested that the smaller, soluble oligomers are more toxic to cells. We are applying computational modeling approaches to uncover the molecular mechanism of misfolding, to determine  driving forces underlying aggregation, to characterize structures of the oligomers and fibril aggregates, and to design therapeutics against aggregation.


22. Pilkington E.H., Xing Y., Wang B., Kakinen A., Wang M., Davis T.P., Ding F., Ke P.C., “Effects of Protein Corona on IAPP Amyloid Aggregation, Fibril Remodelling, and Cytotoxicity”, Scientific Reports, in press (2017)

21. Hadi-Alijanvand, H., Proctor, E. A., Ding, F., Dokholyan, N. V. and Moosavi-Movahedi, A. A. “A Hidden Aggregation-Prone Structure in the Heart of Hypoxia Inducible Factor Prolyl Hydroxylase”, Proteins: Structure, Function and Bioinformatics, in press, (2016)

20. E.N. Gurzov, B. Wang, E.H. Pilkington, P. Chen,A. Kakinen, W.J. Stanley, S.A. Litwak, E.G. Hanssen,T.P. Davis, F. Ding, and P.Chun Ke, “Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-cell Toxicity by OH-terminated PAMAM Dendrimer”, Small, in press (2016)

19. S. Radic, T.P. Davis, P.C. Ke and F. Ding, “Contrasting effects of nanoparticle-protein attraction on amyloid aggregation”, RSC Advances, in press (2015)

18. P. Nedumpully-Govindan, A. Kakinen, E.H. Pilkington, T.P. Davis, P.C. Ke and F. Ding, “Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition”, Scientific Reports, in press (2015)

17. P. Nedumpully-Govindan, E.N. Gurzov, P. Chen, E.H. Pilkington, W.J. Stanley, S.A. Litwak, T.P. Davis, P.C. Ke, and F. Ding, “Graphene Oxide Inhibits hIAPP Amyloid Fibrillation and Toxicity in Insulin-Producing NIT-1 Cells”, PCCP, in press (2015)

16. S. Radic, T.P. Davis, P.C. Ke and F. Ding, “Contrasting effects of nanoparticle-protein attraction on amyloid aggregation”, RSC Advances, in press (2015)

15. Nedumpully-Govindan P. and Ding F., “Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration”, Scientific Reports, in press (2015)

14. F. Ding, Y. Furukawa, N. Nukina, and Dokholyan, N.V., “Local unfolding of Cu, Zn superoxide Dismutase monomer determines the morphology of fibrillar aggregates”, Journal of Molecular Biology, 421:548-560 (2012) [download]

13. Proctor, E. A., F. Ding, and Dokholyan, N. V. “Structural and thermodynamic effects of post-translational modifications in mutant and wild type Cu, Zn superoxide dismutase”, Journal of Molecular Biology, 408:555-567 (2011). [download]

12. V. V. Lakhani, F. Ding and N. V. Dokholyan, “Poly-glutamine induced misfolding of huntingtin exon1 is modulated by the flanking sequences” Public Library of Science Computational Biology:e1000772 (2010) [download]

11. F. Ding and N. V. Dokholyan, “Dynamical roles of metal ions and the disulfide bond in Cu, Zn superoxide dismutase folding and aggregation” Proceedings of the National Academy of Sciences USA, 105:19696-19701 (2008) [download]

10. S. Sharma, F. Ding, and N. V. Dokholyan, “Probing protein aggregation using simplified models and discrete molecular dynamics” Frontiers in Bioscience, 13: 4795-4808 (2008) [download]

9. S. Barton, R. Jacak, S. D. Khare, F. Ding*, and N. V. Dokholyan*, “The length dependence of the polyQ-mediated protein aggregation” Journal of Biological Chemistry, 282: 25487-25492 (2007)[download]

8. F. Ding, K. C. Prutzman, S. L. Campbell, and N. V. Dokholyan, “Topological determinants of protein domain swapping”, Structure, 14: 5-14 (2005). [download][service]

7. F. Ding, J. J. LaRocque, and N. V. Dokholyan, “Direct observation of protein folding, aggregation and a prion-like conformational transition”, Journal of Biological Chemistry, 280: 40235-40240 (2005)[download]

6. S. D. Khare, F. Ding, K. N. Gwanmesia, and N. V. Dokholyan, “Molecular origin of polyglutamine-mediated protein aggregation in neurodegenerative diseases”, PLoS Computational Biology, 1, e30 (2005). [download]

5. B. Urbanc, L. Cruz, F. Ding, D. Sammond, S. Khare, S. V. Buldyrev, H. E. Stanley, and N. V. Dokholyan, “Molecular dynamics simulation of Amyloid beta dimer formation” Biophys. J., 87: 2310-2321 (2004). [download]

4. S. Peng, F. Ding, B. Urbanc, S. V. Buldyrev, L. Cruz , H. E. Stanley, and N. V. Dokholyan, “Discrete molecular dynamics simulations of peptide aggregation” Phys. Rev. E 69: 041908 (2004)[download]

3. S. D. Khare, F. Ding and N. V. Dokholyan, “Folding of Cu,Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis.” J. Mol. Biol, 334, 515-525, 2003[download]

2. F. Ding*, Borreguero J.M., Buldyrev S.V., Stangley H.E. and Dokholyan N.V., A mechanism for alpha-helix to beta-hairpin transition, Proteins: Structure, Function and Genetics, 53:220-228 (2003)[download]

1. F. Ding, Dokholyan N.V., Buldyrev S.V., Stanley H.E. and Shakhnovich E.I. Molecular dynamics simulation of C-Src SH3 aggregation suggests a generic amyloidogenesis mechanism J Mol Biol, 324:851-857 (2002) [download]