title: Ab initio modeling of the herpesvirus VP26 core domain assessed by CryoEM density.
abstract: Efforts in structural biology have targeted the systematic determination of all protein structures through experimental determination or modeling. In recent years, 3-D electron cryomicroscopy (cryoEM) has assumed an increasingly important role in determining the structures of these large macromolecular assemblies to intermediate resolutions (6-10 A). While these structures provide a snapshot of the assembly and its components in well-defined functional states, the resolution limits the ability to build accurate structural models. In contrast, sequence-based modeling techniques are capable of producing relatively robust structural models for isolated proteins or domains. In this work, we developed and applied a hybrid modeling approach, utilizing cryoEM density and ab initio modeling to produce a structural model for the core domain of a herpesvirus structural protein, VP26. Specifically, this method, first tested on simulated data, utilizes the cryoEM density map as a geometrical constraint in identifying the most native-like models from a gallery of models generated by ab initio modeling. The resulting model for the core domain of VP26, based on the 8.5-A resolution herpes simplex virus type 1 (HSV-1) capsid cryoEM structure and mutational data, exhibited a novel fold. Additionally, the core domain of VP26 appeared to have a complementary interface to the known upper-domain structure of VP5, its cognate binding partner. While this new model provides for a better understanding of the assembly and interactions of VP26 in HSV-1, the approach itself may have broader applications in modeling the components of large macromolecular assemblies.
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Baker
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: William J
authors.initials: WJ
authors.lastname: Wedemeyer
authors.forename: Frazer J
authors.initials: FJ
authors.lastname: Rixon
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods*; D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D020285:Cryoelectron Microscopy / Q000379:methods*; D003461:Crystallography / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D036022:Capsid Proteins; C077409:capsid protein VP26, herpes simplex virus type 1