scholarly journals Calibrated Langevin-dynamics simulations of intrinsically disordered proteins

2014 ◽  
Vol 90 (4) ◽  
Author(s):  
W. Wendell Smith ◽  
Po-Yi Ho ◽  
Corey S. O'Hern
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Langevin Dynamics ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Dynamics Simulations

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>

scholarly journals Planar Boronic Graphene and Nitrogenized Graphene Heterostructure for Protein Stretch and Confinement

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1756
Author(s):  
Xuchang Su ◽  
Zhi He ◽  
Lijun Meng ◽  
Hong Liang ◽  
Ruhong Zhou
Keyword(s):  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Electron Tunneling ◽  
Amyloid Β ◽  
Protein Sequencing ◽  
Disordered Proteins ◽  
Force Microscopy ◽  
Intrinsically Disordered ◽  
Atomic Force ◽  
Dynamics Simulations

Single-molecule techniques such as electron tunneling and atomic force microscopy have attracted growing interests in protein sequencing. For these methods, it is critical to refine and stabilize the protein sample to a “suitable mode” before applying a high-fidelity measurement. Here, we show that a planar heterostructure comprising boronic graphene (BC3) and nitrogenized graphene (C3N) sandwiched stripe (BC3/C3N/BC3) is capable of the effective stretching and confinement of three types of intrinsically disordered proteins (IDPs), including amyloid-β (1–42), polyglutamine (Q42), and α-Synuclein (61–95). Our molecular dynamics simulations demonstrate that the protein molecules interact more strongly with the C3N stripe than the BC3 one, which leads to their capture, elongation, and confinement along the center C3N stripe of the heterostructure. The conformational fluctuations of IDPs are substantially reduced after being stretched. This design may serve as a platform for single-molecule protein analysis with reduced thermal noise.

scholarly journals Progressive Phosphorylation Modulates the Self-Association of a Variably Modified Histone H3 Peptide

2021 ◽  
Vol 8 ◽  
Author(s):  
George V. Papamokos ◽  
George Tziatzos ◽  
Dimitrios G. Papageorgiou ◽  
Spyros Georgatos ◽  
Efthimios Kaxiras ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Histone H3 ◽  
Intramolecular Interactions ◽  
Disordered Proteins ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Self Association ◽  
Dynamics Simulations ◽  
Peptide Charge

Protein phosphorylation is a key regulatory mechanism in eukaryotic cells. In the intrinsically disordered histone tails, phosphorylation is often a part of combinatorial post-translational modifications and an integral part of the “histone code” that regulates gene expression. Here, we study the association between two histone H3 tail peptides modified to different degrees, using fully atomistic molecular dynamics simulations. Assuming that the initial conformations are either α-helical or fully extended, we compare the propensity of the two peptides to associate with one another when both are unmodified, one modified and the other unmodified, or both modified. The simulations lead to the identification of distinct inter- and intramolecular interactions in the peptide dimer, highlighting a prominent role of a fine-tuned phosphorylation rheostat in peptide association. Progressive phosphorylation appears to modulate peptide charge, inducing strong and specific intermolecular interactions between the monomers, which do not result in the formation of amorphous or ordered aggregates, as documented by experimental evidence derived from Circular Dichroism and NMR spectroscopy. However, upon complete saturation of positive charges by phosphate groups, this effect is reversed: intramolecular interactions prevail and dimerization of zero-charge peptides is markedly reduced. These findings underscore the role of phosphorylation thresholds in the dynamics of intrinsically disordered proteins. Phosphorylation rheostats might account for the divergent effects of histone modifications on the modulation of chromatin structure.

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.

scholarly journals The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins

2021 ◽  
Vol 22 (20) ◽  
pp. 11058
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Intrinsically Disordered ◽  
Local Contraction ◽  
Charged Residues ◽  
Common Strategy ◽  
Disordered Peptides ◽  
Dynamics Simulations ◽  
The Impact

Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation.

scholarly journals Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison

2021 ◽  
Vol 22 (18) ◽  
pp. 10174
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Salt Bridges ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
The Difference ◽  
Disordered Peptides ◽  
Dynamics Simulations

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study.

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