Huo Group
                                                                Computational Chemistry & Biophysics

     The Native State of Human Transthyretin (Tetramer) Human transthyretin (TTR) amyloid deposits putatively cause several types of amyloid diseases, such as familial amyloid cardiomyopathy and senile systemic amyloidosis, both characterized by TTR amyloid deposits in the heart tissues. Besides TTR, there are about twenty human amyloidogenic proteins, such as lysozyme and Alzheimer¡¯s amyloid peptide (Ab), that can form amyloid fibrils in vivo through conformational changes and self-assembly.  Although these proteins vary in sequence, size, and structure, the X-ray diffraction patterns of the fibrils are strikingly similar, characterized by cross b-structures.  An hypothesis on the formation of similar fibril structures from non-homologous proteins is that while these proteins are not related in their native folded states, their amyloidogenic intermediate conformations share common features upon partial denaturation which facilitates self-assembly into amyloid fibrils.  A careful study of this process will not only intrigue the biophysics community but might also reveal important general principles of molecular recognition and self-assembly for fields as diverse as material science, bioengineering and nanochemistry. We are interested in mapping the early steps of TTR amyloid formation with computational approaches.

Related publications:

D. Li, S. Mohanty, A. Irbäck, S.Huo. Formation and growth of oligomers: A monte carlo study of an amyloid Tau fragment. PLoS Comput. Biol. 4(12), e1000238 (2008).                                                                                                                                                 

D. Li, L. Han, S. Huo. Structural and pathway complexity of β-strand reorganization within aggregates of human Transthyretin(105-115) peptide. J. Phys. Chem. B. 111: 5425-5433 (2007). 

M. Yang, B. Yordanov Y. Levy, R. Brüschweiler, and S. Huo. Sequence-dependent unfolding pathway plays a critical role in the Amyloidogenicity of Transthyretin. Biochemistry. 45: 11992-12002 (2006). 

M. Yang, M. Lei, R. Brüschweiler, S. Huo. Initial conformational changes of human Transthyretin under partially denaturing conditions. Biophys. J. 89: 433-443 (2005). 

M. Lei, M. Yang, S. Huo. Intrinsic versus mutation dependent instability/flexibility: A comparative analysis of the structure and dynamics of wild-type Transthyretin and its pathogenic variants. J. Struct. Biol. 148: 153-168 (2004). 

M. Yang, M. Lei, S. Huo. Why is Leu55Pro55 Transthyretin variant the most amyloidogenic: Insight from molecular dynamics simulations of Transthyetin monomers. Protein Sci. 12: 1222-1231 (2003).
Protein misfolding and amyloid diseases
The Native State of Human Transthyretin (Tetramer)