Longitudinal Spin Order Labeling on Multiple Quantum Coherences Enables NMR Analysis of Intrinsically Disordered Proteins at Ultrahigh Resolution

2021 ◽  
pp. 9315-9320
Author(s):  
Jonghyuk Im ◽  
Kyungryun Lee ◽  
Sohyun Jung ◽  
Eunhee Kim ◽  
Jung Ho Lee
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Multiple Quantum ◽  
Nmr Analysis ◽  
Ultrahigh Resolution ◽  
Spin Order ◽  
Intrinsically Disordered ◽  
Longitudinal Spin

scholarly journals Detecting segmental anisotropic diffusion in disordered proteins by cross-correlated spin-relaxation

2021 ◽  
Author(s):  
Clemens Kauffmann ◽  
Irene Ceccolini ◽  
Georg Kontaxis ◽  
Robert Konrat
Keyword(s):  
Spin Relaxation ◽  
Anisotropic Diffusion ◽  
Intrinsically Disordered Proteins ◽  
Complex Dynamics ◽  
Disordered Proteins ◽  
Multiple Quantum ◽  
Ensemble Averaging ◽  
Intrinsically Disordered ◽  
Folded Proteins ◽  
Spin Pairs

Abstract. Among the numerous contributions of Geoffrey Bodenhausen to NMR spectroscopy his developments in the field of spin-relaxation methodology and theory will definitely have a long lasting impact. Starting with his seminal contributions to the excitation of multiple-quantum coherences he and his group thoroughly investigated the intricate relaxation properties of these “forbidden fruits” and developed experimental techniques to reveal the relevance of previously largely ignored cross-correlated relaxation (CCR) effects, as “the essential is invisible to the eyes”. Here we want to discuss CCR within the challenging context of intrinsically disordered proteins (IDPs) and emphasize its potential and relevance for the studies of structural dynamics of IDPs in the future years to come. Conventionally, dynamics of globularly folded proteins are modeled and understood as deviations from otherwise rigid structures tumbling in solution. However, with increasing protein flexibility, as observed for IDPs, this apparent dichotomy between structure and dynamics becomes blurred. Although complex dynamics and ensemble averaging might impair the extraction of mechanistic details even further, spin-relaxation uniquely encodes a protein’s structural memory, i.e. the temporal persistence of concerted motions and structural arrangements. Due to significant methodological developments, such as high-dimensional non-uniform sampling techniques, spin-relaxation in IDPs can now be monitored in unprecedented resolution. Not embedded within a rigid globular fold, conventional 15N spin probes might not suffice to capture the inherently local nature of IDP dynamics. To better describe and understand possible segmental motions of IDPs, we propose an experimental approach to detect the signature of diffusion anisotropy by quantifying cross-correlated spin relaxation of individual 15N1HN and 13C'13Cα spin pairs. By adapting Geoffrey Bodenhausen’s symmetrical reconversion principle to obtain zero frequency spectral density values we can define and demonstrate more sensitive means to characterize segmental anisotropic diffusion in IDPs.

scholarly journals Detecting anisotropic segmental dynamics in disordered proteins by cross-correlated spin relaxation

2021 ◽  
Vol 2 (2) ◽  
pp. 557-569
Author(s):  
Clemens Kauffmann ◽  
Irene Ceccolini ◽  
Georg Kontaxis ◽  
Robert Konrat
Keyword(s):  
Spin Relaxation ◽  
Intrinsically Disordered Proteins ◽  
Complex Dynamics ◽  
Disordered Proteins ◽  
Multiple Quantum ◽  
Ensemble Averaging ◽  
Segmental Dynamics ◽  
Intrinsically Disordered ◽  
Folded Proteins ◽  
Spin Pairs

Abstract. Among the numerous contributions of Geoffrey Bodenhausen to NMR spectroscopy, his developments in the field of spin-relaxation methodology and theory will definitely have a long lasting impact. Starting with his seminal contributions to the excitation of multiple-quantum coherences, he and his group thoroughly investigated the intricate relaxation properties of these “forbidden fruits” and developed experimental techniques to reveal the relevance of previously largely ignored cross-correlated relaxation (CCR) effects, as “the essential is invisible to the eyes”. Here we consider CCR within the challenging context of intrinsically disordered proteins (IDPs) and emphasize its potential and relevance for the studies of structural dynamics of IDPs in the future years to come. Conventionally, dynamics of globularly folded proteins are modeled and understood as deviations from otherwise rigid structures tumbling in solution. However, with increasing protein flexibility, as observed for IDPs, this apparent dichotomy between structure and dynamics becomes blurred. Although complex dynamics and ensemble averaging might impair the extraction of mechanistic details even further, spin relaxation uniquely encodes a protein's structural memory. Due to significant methodological developments, such as high-dimensional non-uniform sampling techniques, spin relaxation in IDPs can now be monitored in unprecedented resolution. Not embedded within a rigid globular fold, conventional 15N spin probes might not suffice to capture the inherently local nature of IDP dynamics. To better describe and understand possible segmental motions of IDPs, we propose an experimental approach to detect the signature of anisotropic segmental dynamics by quantifying cross-correlated spin relaxation of individual 15N1HN and 13C′13Cα spin pairs. By adapting Geoffrey Bodenhausen's symmetrical reconversion principle to obtain zero frequency spectral density values, we can define and demonstrate more sensitive means to characterize anisotropic dynamics in IDPs.

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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