Mapping the intrinsically disordered properties of the flexible loop domain of Bcl-2: a molecular dynamics simulation study

  • Ian Ilizaliturri-Flores
  • José Correa-Basurto
  • Martiniano Bello
  • Jorge L. Rosas-Trigueros
  • Beatriz Zamora-López
  • Claudia G. Benítez-Cardoza
  • Absalom Zamorano-Carrillo
Original Paper


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.

Graphical Abstract

Emergence of the Bcl-2-rFLD’s structural heterogeneity in solution, evidenced by molecular dynamics simulation.


Bcl-2 Molecular dynamics Intrinsic disorder Flexible loop domain 



This study was conducted thanks to grants from CONACYT, ICyTDF, SIP-IPN(20150301), COFAA-IPN. We also gratefully acknowledge the scholarships from CONACYT to IIF.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ian Ilizaliturri-Flores
    • 1
  • José Correa-Basurto
    • 1
  • Martiniano Bello
    • 1
  • Jorge L. Rosas-Trigueros
    • 2
  • Beatriz Zamora-López
    • 3
  • Claudia G. Benítez-Cardoza
    • 4
  • Absalom Zamorano-Carrillo
    • 4
  1. 1.Lab de Modelado Molecular y Diseño de Fármacos. ESM-IPNCiudad de MéxicoMexico
  2. 2.Lab Transdisciplinario de Investigación en Sistemas Evolutivos, ESCOM-IPNCiudad de MéxicoMexico
  3. 3.Depto de Salud Mental, Facultad de Medicina, UNAMCiudad de MéxicoMexico
  4. 4.Lab de Bioquímica y Biofísica Computacional, ENMH-IPNCiudad de MéxicoMexico

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