Hybrid of Electron Cryo-Microscopy and Bioinformatics to Reveal Protein                      
Folds in Domains of Biological Machines                                                      
                                                                                             
Wah Chiu, Alvin Romansky Professor of Biochemistry and Director of                           
Graduate Program in Structural and Computational Biology and Molecular                       
Biophysics, Baylor College of Medicine, Houston, Texas                                       
                                                                                             
Few large biological machines have been solved to atomic resolution,                         
resulting in under-representation in the library of known structures and                     
folds. Thus, it is likely these large complexes might contain many yet                       
unidentified folds, providing an enriched source of novel folds. However,                    
it is often difficult to achieve a high-resolution model for these                           
structures. Electron cryo-microscopy is capable of determining structures                    
of large assemblies at low to intermediate resolutions. To aid in the                        
interpretation and analysis of such structures, we have developed a                          
computational method to identify potential homologous folds based on the                     
arrangement of alpha helix elements, resulting in a structure-based                          
recognition of folds containing alpha helices. In addition, we can use                       
sequence-based threading to predict fold in a small domain of a large                        
complex and then fit the putative fold within a region of the target
structure. The structural fitting therefore provides a quantitative means
to further examine the architecture and organization of large, complex
machine. Applications of these methods to study large animal virus such as
herpesvirus capsid and skeletal muscle calcium release channel will be
demonstrated.