scholarly journals Extreme Fuzzy Association of an Intrinsically Disordered Protein with Acidic Membranes

2020 ◽  
Author(s):  
Alan Hicks ◽  
Cristian A. Escobar ◽  
Timothy A. Cross ◽  
Huan-Xiang Zhou
Keyword(s):  
Molecular Dynamics ◽  
Solid State Nmr ◽  
Transmembrane Helix ◽  
Intrinsically Disordered Protein ◽  
Membrane Association ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Membrane Tethering ◽  
Dynamics Simulations

AbstractMany physiological and pathophysiological processes, including Mycobacterium tuberculosis (Mtb) cell division, may involve fuzzy membrane association by proteins via intrinsically disordered regions. The fuzziness is extreme when the conformation and pose of the bound protein and the composition of the proximal lipids are all highly dynamic. Here we tackled the challenge in characterizing the extreme fuzzy membrane association of the disordered, cytoplasmic N-terminal region (NT) of ChiZ, an Mtb divisome protein, by combining solution and solid-state NMR spectroscopy and molecular dynamics simulations. In a typical pose, NT is anchored to acidic membranes by Arg residues in the midsection. Competition for Arg interactions between lipids and acidic residues, all in the first half of NT, makes the second half more prominent in membrane association. This asymmetry is accentuated by membrane tethering of the downstream transmembrane helix. These insights into sequence-interaction relations may serve as a paradigm for understanding fuzzy membrane association.

Molecular dynamics simulations of the intrinsically disordered protein amelogenin

2016 ◽  
Vol 35 (8) ◽  
pp. 1813-1823 ◽  
Author(s):  
Alessandra Apicella ◽  
Matteo Marascio ◽  
Vincenzo Colangelo ◽  
Monica Soncini ◽  
Alfonso Gautieri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Dynamics Simulations

scholarly journals High-resolution structural characterization of Noxa, an intrinsically disordered protein, by microsecond molecular dynamics simulations

2015 ◽  
Vol 11 (7) ◽  
pp. 1850-1856 ◽  
Author(s):  
L. Michel Espinoza-Fonseca ◽  
Ameeta Kelekar
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Protein ◽  
Atomic Level ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Functional Features ◽  
Dynamics Simulations

Microsecond molecular dynamics simulations reveal structural and functional features of Noxa, an intrinsically disordered protein, at atomic-level resolution.

scholarly journals Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 381
Author(s):  
Bálint Mészáros ◽  
Borbála Hajdu-Soltész ◽  
András Zeke ◽  
Zsuzsanna Dosztányi
Keyword(s):  
Gene Expression Regulation ◽  
Treatment Options ◽  
Intrinsically Disordered Protein ◽  
System Level ◽  
Alternative Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Cancer Types ◽  
Cancer Drivers

Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

scholarly journals Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics

Biomolecules ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 104-121 ◽  
Author(s):  
Koji Umezawa ◽  
Jinzen Ikebe ◽  
Mitsunori Takano ◽  
Haruki Nakamura ◽  
Junichi Higo
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Site ◽  
Complex Structure ◽  
Intrinsically Disordered Protein ◽  
Bound State ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Dynamics Simulations ◽  
High Flexibility

The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results.

scholarly journals Optimization of Molecular Dynamics Simulations of c-MYC1-88—An Intrinsically Disordered System

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 109 ◽  
Author(s):  
Sandra S. Sullivan ◽  
Robert O.J. Weinzierl
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Proliferation And Apoptosis ◽  
Conventional Structure ◽  
Experimental Approaches ◽  
Dynamics Simulations

Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins.

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