TY - JOUR
T1 - Origin of Internal Friction in Disordered Proteins Depends on Solvent Quality
AU - Zheng, Wenwei
AU - Hofmann, Hagen
AU - Schuler, Benjamin
AU - Best, Robert B.
N1 - Funding Information:
We thank Dmitrii Makarov, Andrea Soranno, Daniel Nettels, and Andreas Vitalis for helpful discussions. W.Z. and R.B.B. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (ZIA DK075104-05). B.S. was supported by the Swiss National Science Foundation. W.Z. thanks Arizona State University for the start-up support. H.H. was supported by the Israel Science Foundation (ISF) Grant 1549/15, the Benoziyo Fund for the Advancement of Science, the Carolito Foundation, the Gurwin Family Fund for Scientific Research, and the Leir Charitable Foundation. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).
Funding Information:
W.Z. and R.B.B. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (ZIA DK075104-05). B.S. was supported by the Swiss National Science Foundation. W.Z. thanks Arizona State University for the start-up support. H.H. was supported by the Israel Science Foundation (ISF) Grant 1549/15, the Benoziyo Fund for the Advancement of Science, the Carolito Foundation, the Gurwin Family Fund for Scientific Research, and the Leir Charitable Foundation.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/12/13
Y1 - 2018/12/13
N2 - Protein dynamics often exhibit internal friction; i.e., contributions to friction that cannot solely be attributed to the viscosity of the solvent. Remarkably, even unfolded and intrinsically disordered proteins (IDPs) exhibit this behavior, despite typically being solvent-exposed. Several competing molecular mechanisms have been suggested to underlie this phenomenon, in particular dihedral relaxation and intrachain interactions. It has also recently been shown that single-molecule data reflecting internal friction in the disordered protein ACTR cannot be explained using polymer models unless this friction is dependent on protein collapse. However, the connection between the collapse of the chain and the underlying mechanism of internal friction has been unclear. To address this issue, we combine molecular simulation and single-molecule experimental data to investigate how chain compaction affects protein dynamics in the context of ACTR. Chain reconfiguration times and internal friction estimated from all-atom simulations are in semiquantitative agreement with experimental data. We dissect the underlying molecular mechanism with all-atom and coarse-grained simulations and clearly identify both intrachain interactions and dihedral angle transitions as contributions to internal friction. However, their relative contribution is strongly dependent on the compactness of the IDP; while dihedral relaxation dominates internal friction in expanded configurations, intrachain interactions dominate for more compact chains. Our results thus imply a continuous transition between mechanisms and provide a link between internal friction in IDPs and that in more compact and folded states of proteins.
AB - Protein dynamics often exhibit internal friction; i.e., contributions to friction that cannot solely be attributed to the viscosity of the solvent. Remarkably, even unfolded and intrinsically disordered proteins (IDPs) exhibit this behavior, despite typically being solvent-exposed. Several competing molecular mechanisms have been suggested to underlie this phenomenon, in particular dihedral relaxation and intrachain interactions. It has also recently been shown that single-molecule data reflecting internal friction in the disordered protein ACTR cannot be explained using polymer models unless this friction is dependent on protein collapse. However, the connection between the collapse of the chain and the underlying mechanism of internal friction has been unclear. To address this issue, we combine molecular simulation and single-molecule experimental data to investigate how chain compaction affects protein dynamics in the context of ACTR. Chain reconfiguration times and internal friction estimated from all-atom simulations are in semiquantitative agreement with experimental data. We dissect the underlying molecular mechanism with all-atom and coarse-grained simulations and clearly identify both intrachain interactions and dihedral angle transitions as contributions to internal friction. However, their relative contribution is strongly dependent on the compactness of the IDP; while dihedral relaxation dominates internal friction in expanded configurations, intrachain interactions dominate for more compact chains. Our results thus imply a continuous transition between mechanisms and provide a link between internal friction in IDPs and that in more compact and folded states of proteins.
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U2 - 10.1021/acs.jpcb.8b07425
DO - 10.1021/acs.jpcb.8b07425
M3 - Article
C2 - 30277791
AN - SCOPUS:85054418541
SN - 1520-6106
VL - 122
SP - 11478
EP - 11487
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 49
ER -