title: Impacts of the G145R Mutation on the Structure and Immunogenic Activity of the Hepatitis B Surface Antigen: A Computational Analysis.
abstract: BACKGROUND
  Vaccine-escaped hepatitis B virus (HBV) mutations occur within the "a" determinant area, which is located in the major hydrophilic region (MHR) of the hepatitis B surface antigen (HBsAg) protein. It is now well established that the common G145R mutation is highly capable of escaping from HBsAg immune recognition. However, the impacts of this mutation on the structure and immunogenic activity of HBsAg have been poorly investigated.
  
  
  OBJECTIVE
  The present study analyzed the effects of the G145R mutation on the structure and immunogenic activity of the HBsAg.
  
  
  METHODS
  Three-dimensional (3D) structure of HBsAg for both the wild-type and G145R mutant were predicted and refined using several web tools. After quantitative evaluations, the effects of the G145R mutation on the secondary and 3D structures of the HBsAg were investigated. In parallel, the immunogenic activity of the wild-type and mutant HBsAg was also analyzed using a ClusPro docking server as well as the IEDB web tool. Further analyses were performed via molecular dynamics (MD) simulations using the GROMACS v5.0.2 simulation package.
  
  
  RESULTS
  The G145R mutation causes a considerable reduction in the immunogenic activity of the HBsAg through a conformational change in the HBsAg antigenic loops. This mutation inserts a new β-strand in the "a" determinant region of the HBsAg, leading to a reduced binding affinity to its monoclonal antibody, MAb12. The G145R mutation also increased the compactness and stability of the HBsAg by enhancing the rigidity of the "a" determinant.
  
  
  CONCLUSIONS
  These data will be beneficial for designing more advanced antibodies for the recognition of the HBsAg in diagnostics. In addition, the results of this study may assist in the design or development of more effective hepatitis B vaccines.
authors.affiliation: Ministry of Health and Medical Education, Deputy of Curative Affairs, Budget Administration, Tehran, IR Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Rezaee
authors.affiliation: Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Mansour
authors.initials: M
authors.lastname: Poorebrahim
authors.affiliation: Department of Microbiology, Tonekabon branch, Islamic Azad University, Tonekabon, Mazandaran, IR Iran.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Najafi
authors.affiliation: Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Solmaz
authors.initials: S
authors.lastname: Sadeghi
authors.affiliation: Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Alieh
authors.initials: A
authors.lastname: Pourdast
authors.affiliation: Middle East Liver Diseases (MELD) Center, Tehran, IR Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.
authors.forename: Seyed Moayed
authors.initials: SM
authors.lastname: Alavian
authors.affiliation: Middle East Liver Diseases (MELD) Center, Tehran, IR Iran; Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Seyed Ehsan
authors.initials: SE
authors.lastname: Alavian
authors.affiliation: Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Vahdat
authors.initials: V
authors.lastname: Poortahmasebi
keywords: G145R Mutation; HBsAg Mutations; Vaccine Escape Mutations