Disordered Motifs and Domains in Cell Control
Poster Session II
27-POS
Board 3
From Chaos to Order: The Association Pathway of RNAse-S
Manuel Luitz
, Rainer Bomblies, Martin Zacharias.
Technical University of Munich, Garching, Germany.
Intrinsically disordered proteins can undergo transitions to ordered folded states upon association
with a receptor protein. The transition pathway from unbound to bound complex is often difficult
to determine experimentally. In case of the RNAse-S system a small S-peptide, disordered in the
unbound state, forms an alpha-helical structure upon binding to the S-protein partner.
The resulting complex forms an active RNAse-S enzyme. Molecular dynamics (MD)
and advanced sampling approaches were used to investigate the coupled folding and binding of
the S-peptide at atomic resolution. In agreement with xperiment significant conformational
fluctuations of the isolated S-Peptide compatible with a disordered state were found. In order to
identify residues which contribute most to the complex affinity and to find possible key contacts
which are formed first on the route to the folded complex we performed in silico alanine
scanning on the all residues of S-Peptide. Phe8 was identified as an anchor residue which
contributes most to the binding free energy along with Met13 and His12 contributing slightly
less to affinity. A pulling imulation on the centers of masses of S-peptide and S-Protein revealed
an unfolding pathway with an initial opening of the S-Peptide helix followed by a
subsequent dissociation of the key contacts. Based on these findings we could trigger complex
formation in several extended MD simulations by closing the key contact of Phe8 with S-Protein
and a disordered initial S-peptide. The subsequent
S-peptide folding process resulted in helix folding emerging from a specific hydrogen bonding
network to stabilize the final helical peptide structure. Comparison with coil-helix transitions of
the S-peptide in solution allowed the characterization of important interactions with the S-protein
that stabilize and promote helix folding.
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