scholarly journals Detection of correlated conformational fluctuations in intrinsically disordered proteins through paramagnetic relaxation interference

2016 ◽  
Vol 18 (8) ◽  
pp. 5753-5758 ◽  
Author(s):  
D. Kurzbach ◽  
A. Vanas ◽  
A. G. Flamm ◽  
N. Tarnoczi ◽  
G. Kontaxis ◽  
...  
Keyword(s):  
Direct Observation ◽  
Intrinsically Disordered Proteins ◽  
Paramagnetic Relaxation ◽  
Disordered Proteins ◽  
Intrinsically Disordered

NMR-based paramagnetic relaxation interference (PRI) allows for direct observation of concerted motions and cooperatively folded sub-states in IDPs, via cross correlated relaxation.

NMR probing and visualization of correlated structural fluctuations in intrinsically disordered proteins

2017 ◽  
Vol 19 (16) ◽  
pp. 10651-10656 ◽  
Author(s):  
Dennis Kurzbach ◽  
Andreas Beier ◽  
Agathe Vanas ◽  
Andrea G. Flamm ◽  
Gerald Platzer ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Statistical Analysis ◽  
Magnetic Resonance ◽  
Intrinsically Disordered Proteins ◽  
Paramagnetic Relaxation ◽  
Disordered Proteins ◽  
Correlation Matrices ◽  
Intrinsically Disordered ◽  
Nmr Data ◽  
Structural Fluctuations

A novel statistical analysis of paramagnetic relaxation enhancement (PRE) and paramagnetic relaxation interference (PRI) based nuclear magnetic resonance (NMR) data is proposed based on the computation of correlation matrices.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Heterogeneous Polymer ◽  
Non Local ◽  
Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

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