Discrete molecular dynamics can predict helical prestructured motifs in disordered proteins

Dániel Szöllosi, Tamás Horváth, Kyou Hoon Han, Nikolay V. Dokholyan, Péter Tompa, Lajos Kalmár, Tamás Hegedus

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Intrinsically disordered proteins (IDPs) lack a stable tertiary structure, but their short binding regions termed Pre-Structured Motifs (PreSMo) can form transient secondary structure elements in solution. Although disordered proteins are crucial in many biological processes and designing strategies to modulate their function is highly important, both experimental and computational tools to describe their conformational ensembles and the initial steps of folding are sparse. Here we report that discrete molecular dynamics (DMD) simulations combined with replica exchange (RX) method efficiently samples the conformational space and detects regions populating α-helical conformational states in disordered protein regions. While the available computational methods predict secondary structural propensities in IDPs based on the observation of protein-protein interactions, our ab initio method rests on physical principles of protein folding and dynamics. We show that RX-DMD predicts α-PreSMos with high confidence confirmed by comparison to experimental NMR data. Moreover, the method also can dissect α-PreSMos in close vicinity to each other and indicate helix stability. Importantly, simulations with disordered regions forming helices in X-ray structures of complexes indicate that a preformed helix is frequently the binding element itself, while in other cases it may have a role in initiating the binding process. Our results indicate that RX-DMD provides a breakthrough in the structural and dynamical characterization of disordered proteins by generating the structural ensembles of IDPs even when experimental data are not available.

Original languageEnglish (US)
Article numbere95795
JournalPloS one
Volume9
Issue number4
DOIs
StatePublished - Apr 24 2014

Fingerprint

molecular dynamics
Molecular Dynamics Simulation
Molecular dynamics
Intrinsically Disordered Proteins
Proteins
proteins
Biological Phenomena
Protein folding
Protein Folding
Computational methods
protein folding
protein-protein interactions
methodology
Nuclear magnetic resonance
Observation
X-Rays
X-radiation
X rays
Computer simulation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Szöllosi, Dániel ; Horváth, Tamás ; Han, Kyou Hoon ; Dokholyan, Nikolay V. ; Tompa, Péter ; Kalmár, Lajos ; Hegedus, Tamás. / Discrete molecular dynamics can predict helical prestructured motifs in disordered proteins. In: PloS one. 2014 ; Vol. 9, No. 4.
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Discrete molecular dynamics can predict helical prestructured motifs in disordered proteins. / Szöllosi, Dániel; Horváth, Tamás; Han, Kyou Hoon; Dokholyan, Nikolay V.; Tompa, Péter; Kalmár, Lajos; Hegedus, Tamás.

In: PloS one, Vol. 9, No. 4, e95795, 24.04.2014.

Research output: Contribution to journalArticle

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AU - Szöllosi, Dániel

AU - Horváth, Tamás

AU - Han, Kyou Hoon

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