title: Mapping the intrinsically disordered properties of the flexible loop domain of Bcl-2: a molecular dynamics simulation study.
abstract: Most of the B-cell lymphoma-2 (Bcl-2) protein structure has been elucidated; however, the conformation of its flexible loop domain (FLD) has not yet been experimentally predicted. Its high flexibility under physiological conditions is the reason. FLD behaves as an intrinsically disordered region (IDR) and can adopt regular structures in particular conditions associated with the control of Bcl-2's anti-apoptotic functions. In a previous contribution, we analyzed an engineered Bcl-2 construct (Bcl-2-Δ22Σ3) submitted to 25-ns MD and reported a disordered-to-helix transitions in a region of FLD (rFLD, residues 60-77). However, the conformational preferences in solution of rFLD in the nanosecond to microsecond scale were not analyzed. Herein, an average model was obtained for the native Bcl-2 protein by homology modeling and MD simulation techniques. From this, only the atomic coordinates corresponding to the rFLD were simulated for 1 μs by MD at 310 K. In concordance with previous studies, a disordered-to-helix transitions were exhibited, implying that this "interconversion of folding" in the rFLD suggest a possible set of conformations encoded in its sequence. Principal component analysis (PCA) showed that most of the conformational fluctuation of Bcl-2 is provided by rFLD. Dihedral PCA (dPCA) offered information about all the conformations of rFLD in the μs of the simulation, characterizing a dPCA-based free energy landscape of rFLD, and a conformational ensemble of fast interconverting conformations as other IDRs. Furthermore, despite the conformational heterogeneity of rFLD, the analysis of the dihedral angles (Φ, Ψ) showed that this region does not randomly explore the conformational space in solution.
authors.affiliation: Lab de Modelado Molecular y Diseño de Fármacos. ESM-IPN, Ciudad de México, Mexico.
authors.forename: Ian
authors.initials: I
authors.lastname: Ilizaliturri-Flores
authors.affiliation: Lab de Modelado Molecular y Diseño de Fármacos. ESM-IPN, Ciudad de México, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Lab de Modelado Molecular y Diseño de Fármacos. ESM-IPN, Ciudad de México, Mexico.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Bello
authors.affiliation: Lab Transdisciplinario de Investigación en Sistemas Evolutivos, ESCOM-IPN, Ciudad de México, Mexico.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Rosas-Trigueros
authors.affiliation: Depto de Salud Mental, Facultad de Medicina, UNAM, Ciudad de México, Mexico.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Zamora-López
authors.affiliation: Lab de Bioquímica y Biofísica Computacional, ENMH-IPN, Ciudad de México, Mexico.
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Benítez-Cardoza
authors.affiliation: Lab de Bioquímica y Biofísica Computacional, ENMH-IPN, Ciudad de México, Mexico. azamorano@ipn.mx.
authors.forename: Absalom
authors.initials: A
authors.lastname: Zamorano-Carrillo
keywords: Bcl-2; Flexible loop domain; Intrinsic disorder; Molecular dynamics