TY - JOUR
T1 - Characterization of the free state ensemble of the CoRNR box motif by molecular dynamics simulations
AU - Cino, E.A.
AU - Choy, W.Y.
AU - Karttunen, M.E.J.
PY - 2016/2/18
Y1 - 2016/2/18
N2 - Intrinsically disordered proteins (IDPs) and regions are highly prevalent in eukaryotic proteomes, and like folded proteins, they perform essential biological functions. Interaction sites in folded proteins are generally formed by tertiary structures, whereas IDPs use short segments called linear motifs (LMs). Despite their short length and lack of stable structure, LMs may have considerable structural propensities, which often resemble bound-state conformations with targets. Structural data is crucial for understanding the molecular basis of protein interactions and development of targeted pharmaceuticals, but IDPs present considerable challenges to experimental techniques. As a result, IDPs are largely underrepresented in the Protein Data Bank. In the face of experimental challenges, molecular dynamics (MD) simulations have proven to be a useful tool for structural characterization of IDPs. Here, the free state ensemble of the nuclear receptor corepressor 1 (NCOR1) CoRNR box 3 motif, which is important for binding to nuclear receptors to control gene expression, is studied using MD simulations of a total of 8 μs. Transitions between disordered and α-helical conformations resembling a bound-state structure were observed throughout the trajectory, indicating that the motif may have a natural conformational bias toward bound-state structures. The data shows that the disordered and folded populations are separated by a low energy (4-6 kJ/mol) barrier, and the presence of off-pathway intermediates, leading to a C-terminally folded species that cannot efficiently transition into a completely folded conformation. Structural transitions and folding pathways within the free state ensemble were well-described by principal component analysis (PCA) of the peptide backbone dihedral angles, with the analysis providing insight for increasing structural homogeneity of the ensemble.
AB - Intrinsically disordered proteins (IDPs) and regions are highly prevalent in eukaryotic proteomes, and like folded proteins, they perform essential biological functions. Interaction sites in folded proteins are generally formed by tertiary structures, whereas IDPs use short segments called linear motifs (LMs). Despite their short length and lack of stable structure, LMs may have considerable structural propensities, which often resemble bound-state conformations with targets. Structural data is crucial for understanding the molecular basis of protein interactions and development of targeted pharmaceuticals, but IDPs present considerable challenges to experimental techniques. As a result, IDPs are largely underrepresented in the Protein Data Bank. In the face of experimental challenges, molecular dynamics (MD) simulations have proven to be a useful tool for structural characterization of IDPs. Here, the free state ensemble of the nuclear receptor corepressor 1 (NCOR1) CoRNR box 3 motif, which is important for binding to nuclear receptors to control gene expression, is studied using MD simulations of a total of 8 μs. Transitions between disordered and α-helical conformations resembling a bound-state structure were observed throughout the trajectory, indicating that the motif may have a natural conformational bias toward bound-state structures. The data shows that the disordered and folded populations are separated by a low energy (4-6 kJ/mol) barrier, and the presence of off-pathway intermediates, leading to a C-terminally folded species that cannot efficiently transition into a completely folded conformation. Structural transitions and folding pathways within the free state ensemble were well-described by principal component analysis (PCA) of the peptide backbone dihedral angles, with the analysis providing insight for increasing structural homogeneity of the ensemble.
UR - http://www.scopus.com/inward/record.url?scp=84959356306&partnerID=8YFLogxK
U2 - 10.1021/acs.jpcb.5b11565
DO - 10.1021/acs.jpcb.5b11565
M3 - Article
C2 - 26794929
AN - SCOPUS:84959356306
SN - 1520-6106
VL - 120
SP - 1060
EP - 1068
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 6
ER -