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Comparative Molecular Dynamics Analysis of RNase-S Complex Formation.

Abstract：

:Limited proteolysis of RNase-A yields a short N-terminal S-peptide segment and the larger S-protein. Binding of S-peptide to S-protein results in the formation of an enzymatically active RNase-S protein. S-peptide undergoes a transition from intrinsic disorder to an ordered helical state upon association with S-protein to form RNase-S and is an excellent model system to study coupled folding and binding. To better understand the dynamics of the RNases-S complex and its isolated partners, comparative molecular dynamics simulations have been performed. In agreement with experiment, we find significant conformational fluctuations of the isolated S-peptide compatible with a disordered regime and only little residual helical structure. In the RNase-S complex, the N-terminal helix of S-peptide unfolds and refolds repeatedly on the microsecond timescale, indicating that the α-helical structure is only part of the equilibrium regime for these residues whereas the C-terminal residues are confined to the helical conformation that is found in the x-ray structure. This is also in line with systematic, in silico Alanine scanning free-energy simulations, which indicate that the major contribution to complex stability emerges from the C-terminal helical turn, consisting of residues 8-13 in S-peptide whereas the N-terminal S-peptide residues 1-7 make only minor contributions. Comparative simulations of S-protein in the presence and absence of S-peptide reveal that the isolated S-protein is significantly more flexible than in the complex, and undergoes a global pincerlike conformational change that narrows the S-peptide binding cleft. The narrowed binding cleft adds a barrier for complex formation likely influencing the binding kinetics. This conformational change is reversed by S-peptide association, which also stabilizes conformational fluctuations in S-protein. Such global motions associated with binding are also likely to play a role for other coupled peptide folding and binding processes at peptide binding regions on protein surfaces.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Luitz MP,Bomblies R,Zacharias M

doi

10.1016/j.bpj.2017.08.008

subject

Has Abstract

pub_date

2017-10-03 00:00:00

pages

1466-1474

issue

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(17)30865-2

journal_volume

113

pub_type

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Comparative Molecular Dynamics Analysis of RNase-S Complex Formation.