title: Exploring the conformational and binding properties of unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 through docking and molecular dynamics simulations.
abstract: B-cell lymphoma (Bcl-2) is commonly associated with the progression and preservation of cancer and certain lymphomas; therefore, it is considered as a biological target against cancer. Nevertheless, evidence of all its structural binding sites has been hidden because of the lack of a complete Bcl-2 model, given the presence of a flexible loop domain (FLD), which is responsible for its complex behavior. FLD region has been implicated in phosphorylation, homotrimerization, and heterodimerization associated with Bcl-2 antiapoptotic function. In this contribution, homology modeling, molecular dynamics (MD) simulations in the microsecond (µs) time-scale and docking calculations were combined to explore the conformational complexity of unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 systems. Conformational ensembles generated through MD simulations allowed for identifying the most populated unphosphorylated/phosphorylated monomeric conformations, which were used as starting models to obtain trimeric complexes through protein-protein docking calculations, also submitted to µs MD simulations. Principal component analysis showed that FLD represents the main contributor to total Bcl-2 mobility, and is affected by phosphorylation and oligomerization. Subsequently, based on the most representative unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 conformations, docking studies were initiated to identify the ligand binding site of several known Bcl-2 inhibitors to explain their influence in homo-complex formation and phosphorylation. Docking studies showed that the different conformational states experienced by FLD, such as phosphorylation and oligomerization, play an essential role in the ability to make homo and hetero-complexes. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 393-413, 2016.
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México.
authors.forename: Oscar J
authors.initials: OJ
authors.lastname: Zacarías-Lara
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Bello
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D006072:Gossypol / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009596:Nitrophenols / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry*; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry; D025341:Principal Component Analysis; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; C000595707:BCL2 protein, human; D001713:Biphenyl Compounds; D008024:Ligands; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D006072:Gossypol; D017239:Paclitaxel; C528561:navitoclax
keywords: Bcl-2; clustering analysis; docking calculations; molecular dynamics simulations; principal component analysis