Computational Chemistry, Biophysics
Associate Professor of Chemistry
Biochemistry and Molecular Biology Program
Worcester, MA 01610-1477
Office: S235, Sackler Sciences Center
Postdoctoral Fellow, University of California, San Francisco, 1999-2001
Ph.D. Boston University, 1999
B.S. Peking University, 1990
Current Research and Teaching
Our research will focus on computer simulation of molecular interactions in complex systems, particularly protein-protein interactions and protein-small molecule interactions, computer aided structure-based drug design, and development of novel computational algorithms to study enzyme reaction mechanism.
Ongoing Projects Include
I. Protein misfolding and amyloid diseases. 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 (AI. Protein misfolding and amyloid diseases. 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.
II. Monitoring HIV-1 Tat protein function by molecular dynamics simulation. The Tat protein of HIV-1 is a key transcriptional regulator of viral replication. Tat binds a specific structure of transcribed RNA and recruits distinct protein complexes to the viral promoter. Tat is engages three prominent types of protein-protein interactions: those with general transcription factors, those with the transcriptional co-activators and histone acetyltransferases p300/CBP and P/CAF capable of modifying histones and Tat itself, and those with kinase complexes able to promote RNA pol II elongation. To gain insights into these processes and identify new partners that function in/or regulate the process, we team up with three international groups: Alessandro Marcello at ICGEB, Vittorio Pellegrini at NEST, and Monsef Benkirane at IGH. Using a large variety of biomolecular techniques including computer simulations to investigate the specific interactions of Tat in vivo, their spatial and temporal dynamics, their regulation by post-translational modifications and their control by innovative pharmacology are at the core of this project. We won the Human Frontier Science Program Young Investigators’ Award.
M. Duan, J. Fan, and S. Huo. "Conformations of Islet Amyloid Polypeptide Monomers in a Membrane Environment: Implications for Fibril Formation". PLoS ONE 7(11): e47150 (2012).
H. Liu, S. Huo. "Effects of two solvent conditions on the free energy landscape of the BBL peripheral subunit binding domain". J. Phys. Chem. B. 116: 646-652 (2012).
J. Fan, M. Duan, D. Li, H. Wu, H. Yang, L. Han, S. Huo. "Observation of two families of folding pathways of BBL". Biophys. J. 100: 2457-2465 (2011).
H. Wu, A. Canfield, J. Adhikari, S. Huo. "Quantum mechanical studies on model alpha-pleated sheets". J Comput. Chem. 31: 1216-1223 (2010).
D. Li, H. Yang, L. Han, S. Huo, "Predicting the Folding Pathway of Engrailed Homeodomain with a Probabilistic Roadmap Enhanced Reaction-Path Algorithm", Biophysical J. 94, 1622-1629, 2008.
D. Li, L. Han, S. Huo, "Structural and Pathway Complexity of ß-Strand Reorganization with Aggregates of Human Transthyretin(105-115) Peptide", J. Phys. Chem. B 111, 5425-5433, 2007.
H. Yang, H. Wu, D. Li, L. Han, S. Huo, "Temperature-Dependent Probabilistic Roadmap Algorithm for Calculating Variationally Optimized Conformational Transition Pathways", J. Chem. Theory. Comput. 3, 17-25, 2007.
D. Li, M. Khanlarzadeh, J. Wang, S. Huo, R. Brüschweiler, "Evaluation of Configurational Entropy Methods from Peptide Folding -- Unfolding Simulation", J. Phys. Chem. B 111, 13807-13812, 2007.
M. Yang, M. Lei, B. Yordanov, S. Huo, "Peptide Plane Can Flip in Two Opposite Directions: Implication in Amyloid Formation of Transthyretin", J. Phys. Chem. B 110: 5829-5833, 2006.
M. Yang, M. Lei, R. Bruschweiler, S. Huo, "Initial conformational changes of human transthyretin under partially denaturing conditions", Biophysical Journal 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 Leu55g Transthretin Variant the Most Amyloidogenic: Insight from Molecular dynamics Simulations of Transthyetin Monomers", Protein Sci. 12: 1222-1231, 2003.
S. Huo, I. Massova, P.A. Kollman, "Computational Alancanning of the 1:1 Human Growth Hormone-Receptor Complex", J. Comput. Chem. 23: 15-27, 2002.
J.E. Straub, J. Guevara, S. Huo, J.P. Lee, "Long Time Dynamic Simulations: Exploring the Folding Pathways of an Alzheimer's Amyloid Abeta-Peptide", Acc. Chem. Res. 35: 473-481, 2002.
S. Huo, J. Wang, P. Cieplak, P.A. Kollman, I.D. Kuntz, "Molecular Dynamics and Free Energy Analysises of Cathespin D-Inhibitor Interactions: Insight into Structure-Based Ligand Design", J. Med. Chem. 45:1412-1419, 2002.
P.A. Kollman, I. Massova, C. Reyes, B. Kuhn, S. Huo, et al. "Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Model", Acc. Chem. Res. 33: 889-897, 2000.