Zhang Lab

The success of the last decade’s genome sequencing efforts has changed the face of biology and medical sciences forever. However, the DNA sequences themselves do not directly provide insight into what each molecule does in living cells. The long-term goal of this laboratory is to develop new bioinformatic approaches to extract structural and functional insights from genome sequences and to help us understand the underlying relationship between sequence, structure, and function.

Our current focuses are: (1), developing computational algorithms to generate large-scale, high-throughput, and reliable predictions of 3-dimensional protein structures from amino acid sequences. The functional insights can therefore be obtained by matching the global topology and active site of the predicted high-resolution structures to the known structure/function databases. (2), modeling the specificities of the protein-protein and protein-ligand interactions. These include docking the predicted/solved monomer structures into multimer structures, and/or generate multimer conformations directly from amino acid sequences by extending the current successful monomer simulation approaches. (3), studies of the reverse process of protein structure prediction, i.e. designing new sequences to create novel proteins of desired structure and function. Protein design is on its own of great biological interest because it provides opportunities for developing new drugs and therapeutics. It will also provide helpful insights and stringent tests of our current understanding of fundamental principles underlying sequence, structure and function. (4), constructing new dynamic models for the understanding of the mechanics of spider capture silk. Spider silk is a natural material produced by orb-web weaving spiders that has a high tensile strength comparable to steel; but unlike steel, it is also extremely resilient with the ability to be stretched to 10 times without breaking. Our purpose is to simulate in real time the dynamic process and the elastic response of the spider silk molecules under external stretching forces. This effort will provide a route to solving the puzzle of what mechanism underlies the high tenacity and extensibility of the spider capture silk, which will also lend insights to the genetic design of special proteins like spider silk molecules.

Representative Publications

• Y. Zhang, I. A. Hubner, A. K. Arakaki, E. Shakhnovich, J. Skolnick. On the origin and highly likely completeness of single-domain protein structures. Proc Natl Acad Sci USA 103, 2605 (2006)
• Y. Zhang, M. E. DeVries, J. Skolnick. Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol 2, e13 (2006)
• Y. Zhang, J. Skolnick. The protein structure prediction problem could be solved using the current PDB library. Proc Natl Acad Sci USA 102, 1029 (2005)
• H. J. Zhou and Y. Zhang. A hierarchical chain model of spider capture silk elasticity. Phys Rev Lett 94, 028104 (2005)
• Y. Zhang, J. Skolnick. TM-align: a protein structure alignment algorithm based on the TM-score. Nucleic Acids Res 33, 2302 (2005)
• Y. Zhang, J. Skolnick. Tertiary structure predictions on a comprehensive benchmark of medium to large size proteins. Biophys J 87, 2647 (2004)
• Y. Zhang, J. Skolnick. Automated structure prediction of weakly homologous proteins on a genomic scale. Proc Natl Acad Sci USA 101, 7594 (2004)
• Y. Zhang, J. Skolnick. A scoring function for the automated assessment of protein structure template quality. Proteins 57, 702 (2004)
• Y. Zhang, J. Skolnick. SPICKER: Approach to clustering protein structures for near-native model selection. J Comp Chem 25, 865 (2004)
• Y. Zhang, A. Kolniski, J. Skolnick. Touchstone II: A new approach to ab initio protein Structure Prediction. Biophys J 85, 1145 (2003)
• M. Dessinges, B. Maier, Y. Zhang, M. Peliti, D. Bensimon, and V. Croquette. Stretching ssDNA, a model polyelectrolyte. Phys Rev Lett 89, 248102 (2002)
• D. Kihara, Y. Zhang, H. Lu, A. Kolinski, J. Skolnick. Ab initio protein structure prediction on a genomic scale: Application to the Mycoplasma Genitalium Genome. Proc Natl Acad Sci USA 99, 5993 (2002)
• Y. Zhang, D. Kihara, J. Skolnick. Local energy landscape flattening: Parallel hyperbolic Monte Carlo sampling of protein folding. Proteins 48, 192 (2002)
• H. J. Zhou, Y. Zhang, Z. C. Ouyang, X. Z. Feng, S. M. Lindsay, P. Balagurumoorthy, R. E. Harrington. Conformation and rigidity of DNA microcircles containing wafl response element for p53 regulatory protein. J Mol Bio 306, 227 (2001)
• Y. Zhang, J. Skolnick. Parallel-hat tempering: A Monte Carlo search scheme for the identification of low-energy structures. J Chem Phys 115, 5027 (2001)
• Y. Zhang, H. J. Zhou, Z. C. Ouyang. Stretching single-stranded DNA: Interplay of electrostatic, base-pairing, and basepair stacking interactions. Biophys J 81, 1133 (2001)