Determination of pKa Values in Intrinsically Disordered Proteins

2020 ◽  
pp. 319-336
Author(s):  
Brandon Payliss ◽  
Anthony Mittermaier
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Pka Values ◽  
Intrinsically Disordered

scholarly journals Quantitative Determination of the Conformational Properties of Partially Folded and Intrinsically Disordered Proteins Using NMR Dipolar Couplings

Structure ◽  
2009 ◽  
Vol 17 (9) ◽  
pp. 1169-1185 ◽  
Author(s):  
Malene Ringkjøbing Jensen ◽  
Phineus R.L. Markwick ◽  
Sebastian Meier ◽  
Christian Griesinger ◽  
Markus Zweckstetter ◽  
...  
Keyword(s):  
Quantitative Determination ◽  
Intrinsically Disordered Proteins ◽  
Dipolar Couplings ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Conformational Properties

scholarly journals Recent Developments in Data-Assisted Modeling of Flexible Proteins

2021 ◽  
Vol 8 ◽  
Author(s):  
Cezary Czaplewski ◽  
Zhou Gong ◽  
Emilia A. Lubecka ◽  
Kai Xue ◽  
Chun Tang ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Disordered Proteins ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Recent Developments ◽  
Dynamic Structures ◽  
Chemical Cross Linking

Many proteins can fold into well-defined conformations. However, intrinsically-disordered proteins (IDPs) do not possess a defined structure. Moreover, folded multi-domain proteins often digress into alternative conformations. Collectively, the conformational dynamics enables these proteins to fulfill specific functions. Thus, most experimental observables are averaged over the conformations that constitute an ensemble. In this article, we review the recent developments in the concept and methods for the determination of the dynamic structures of flexible peptides and proteins. In particular, we describe ways to extract information from nuclear magnetic resonance small-angle X-ray scattering (SAXS), and chemical cross-linking coupled with mass spectroscopy (XL-MS) measurements. All these techniques can be used to obtain ensemble-averaged restraints or to re-weight the simulated conformational ensembles.

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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