Structural Bioinformatics Based Protein Design

The completion of the sequencing of human genome and many other species result in the identification of many potential drug targets. The development of protein therapeutics and research of protein interaction networks require selective protein inhibitors and design of function and property of proteins. The Structural Genomics Project has disclosed crystal structures of more and more proteins. Structural bioinformatics based rational protein design will play important role in biological research and development of protein therapeutics in the post genome era.In this work, we first improved and implemented a complex structure based three dimensional cluster analysis and identified the conserved functional epitopes of two component signal transduction systems. In addition, we identified the specificity determining residues and improved the prediction of protein functional sites by comparing the residue conservation with its structural environment. The residues identified may be used as potential drug targets. Second, we modeled the complex structures of furin/kexin proprotein processing proteases with its inhibitors eglin c mutants and calculated their electrostatic interaction energy. The electrostatic interactions play an important role in inhibitory activity and determining substrate specificity of furin/kexin. Electrostatic mutation method might offer a viable strategy in the rational design of novel specific inhibitors. Third, we implemented virtual screening of protein sequence which is compatible with a target fold using self-consistent ensemble optimization-based protein design method. A Dreiding-based force field is used the design program. This method has been successfully used in the redesign of the property of protein therapeutics and full sequence design of a novel fold. Our method has vast screening ability. It is a practical tool in the engineering of protein function and property or in the research of protein folding.