scholarly journals Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics

2020 ◽  
Vol 1868 (10) ◽  
pp. 140474
Author(s):  
Abhirup Bandyopadhyay ◽  
Sankar Basu
Keyword(s):  
Phase Transition ◽  
Intrinsically Disordered Proteins ◽  
Salt Bridge ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Self Similar ◽  
Bridge Dynamics

scholarly journals Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: probed by salt-bridge dynamics

2020 ◽  
Author(s):  
Abhirup Bandyopadhyay ◽  
Sankar Basu
Keyword(s):  
Phase Transition ◽  
Intrinsically Disordered Proteins ◽  
Complex Structure ◽  
Salt Bridge ◽  
Disordered Proteins ◽  
Structural Basis ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Self Similar ◽  
Bridge Dynamics

AbstractIntrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to the dominant class of cytosolic globular proteins, they harbor an enormous amount of physical flexibility and structural plasticity enforcing them to be retained in conformational ensembles rather than well defined stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of saltbridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope ‘selforganized criticality’ (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their multi-functionality. In accordance with the transient nature of ‘salt-bridge dynamics’, the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in structural conformations of different IDPs. Also, as discussed in the conclusion, the study has the potential to benefit structural tinkering of bio-medically relevant IDPs in the design of biotherapeutics against them.

scholarly journals Salt-bridge Dynamics in Intrinsically Disordered Proteins: A trade-off between electrostatic interactions and structural flexibility

2017 ◽  
Author(s):  
Sankar Basu ◽  
Parbati Biswas
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Salt Bridge ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Trade Off ◽  
Local Rigidity ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Oppositely Charged

AbstractIntrinsically Disordered Proteins (IDPs) are enriched in charged and polar residues; and, therefore, electrostatic interactions play a predominant role in their dynamics. In order to remain multi-functional and exhibit their characteristic binding promiscuity, they need to retain considerable dynamic flexibility. At the same time, they also need to accommodate a large number of oppositely charged residues, which eventually lead to the formation of salt-bridges, imparting local rigidity. The formation of salt-bridges therefore oppose the desired dynamic flexibility. Hence, there appears to be a meticulous trade-off between the two mechanisms which the current study attempts to unravel. With this objective, we identify and analyze salt-bridges, both as isolated as well as composite ionic bond motifs, in the molecular dynamic trajectories of a set of appropriately chosen IDPs. Time evolved structural properties of these salt-bridges like persistence, associated secondary structural ′order-disorder′ transitions, correlated atomic movements, contribution in the overall electrostatic balance of the proteins have been studied in necessary detail. The results suggest that the key to maintain such a trade-off over time is the continuous formation and dissolution of salt-bridges with a wide range of persistence. Also, the continuous dynamic interchange of charged-atom-pairs (coming from a variety of oppositely charged side-chains) in the transient ionic bonds supports a model of dynamic flexibility concomitant with the well characterized stochastic conformational switching in these proteins. The results and conclusions should facilitate the future design of salt-bridges as a mean to further explore the disordered-globular interface in proteins.

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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