title: Molecular dynamics simulations of retinoblastoma protein.
abstract: Tumor suppressor proteins play a crucial role in cell cycle regulation. Retinoblastoma protein (pRB) is one among them which regulates G1-S transition by binding with transcription factors. The activity of pRB is deregulated by cyclin dependent kinases-mediated hyper-phosphorylation and also due to cancer-derived mutations. In addition, it is also deactivated by binding of viral onco-proteins such as large T antigen, E1A, and E7. These viral proteins initially recognize pRB through their conserved LxCxE motif and facilitate dissociation of preexisting pRB-E2F complex. Based on these features, molecular dynamics (MD) simulation is performed for four different states of pRB for which the crystal structure is available. The unliganded/apo form and complex forms with E2F and E7 peptides reveal the molecular mechanism behind the activation and inactivation of pRB. In addition, the ternary complex of pRB with both E7 and E2F (for which no crystal structure is available) is modeled and simulated to understand the influence of binding of one ligand on the other. The variations in the three major factors such as conformational changes, inter- and intra-molecular interactions, and binding free energies between the apo and complex forms confirm the possibility for designing a small molecule inhibitor to inhibit pRB-E7 interactions without altering the prebound E2F. The present study deals with the molecular modeling and MD simulations of pRB in free and ligand-bound forms and confirms that pRB could be a valid target for the anticancer drug design when the cancer is induced by the viral onco-proteins and forms a clear base for designing E7 antagonists.
authors.affiliation: a Centre of Advanced Study in Crystallography and Biophysics, University of Madras , Maraimalai (Guindy) Campus, Chennai , 600025 , India .
authors.forename: C
authors.initials: C
authors.lastname: Ramakrishnan
authors.forename: V
authors.initials: V
authors.lastname: Subramanian
authors.forename: K
authors.initials: K
authors.lastname: Balamurugan
authors.forename: D
authors.initials: D
authors.lastname: Velmurugan
mesh_terms: D050684:E2F Transcription Factors / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D050725:Papillomavirus E7 Proteins / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D016160:Retinoblastoma Protein / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D050684:E2F Transcription Factors; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein