Use of essential and molecular dynamics to study γB-crystallin unfolding after non-enzymic post-translational modifications

2003 ◽  
Vol 27 (4-5) ◽  
pp. 507-510 ◽  
Author(s):  
M.James C. Crabbe ◽  
Lee R. Cooper ◽  
David W. Corne
Keyword(s):  
Molecular Dynamics ◽  
Post Translational Modifications

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

Translocation intermediates of ubiquitin through an α-hemolysin nanopore: implications for detection of post-translational modifications

Nanoscale ◽  
2019 ◽  
Vol 11 (20) ◽  
pp. 9920-9930 ◽  
Author(s):  
Emma Letizia Bonome ◽  
Fabio Cecconi ◽  
Mauro Chinappi
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Post Translational Modifications ◽  
Dynamics Simulations

Molecular dynamics simulations allowed to characterize the co-translocational unfolding pathway of ubiquitin through a biological nanopore.

scholarly journals Biased Brownian Motion of KIF1A and the Role of Tubulin’s C-Terminal Tail Studied by Molecular Dynamics Simulation

2021 ◽  
Vol 22 (4) ◽  
pp. 1547
Author(s):  
Yukinobu Mizuhara ◽  
Mitsunori Takano
Keyword(s):  
Molecular Dynamics ◽  
Brownian Motion ◽  
Energy Landscape ◽  
Dynamics Simulation ◽  
Long Distance ◽  
Post Translational Modifications ◽  
Family Protein ◽  
Dynamics Simulations ◽  
Kinesin Family

KIF1A is a kinesin family protein that moves over a long distance along the microtubule (MT) to transport synaptic vesicle precursors in neurons. A single KIF1A molecule can move toward the plus-end of MT in the monomeric form, exhibiting the characteristics of biased Brownian motion. However, how the bias is generated in the Brownian motion of KIF1A has not yet been firmly established. To elucidate this, we conducted a set of molecular dynamics simulations and observed the binding of KIF1A to MT. We found that KIF1A exhibits biased Brownian motion along MT as it binds to MT. Furthermore, we show that the bias toward the plus-end is generated by the ratchet-like energy landscape for the KIF1A-MT interaction, in which the electrostatic interaction and the negatively-charged C-terminal tail (CTT) of tubulin play an essential role. The relevance to the post-translational modifications of CTT is also discussed.

Computational insights into the structure and dynamics of the human serotonin transporter N-terminus by microsecond molecular dynamics

2020 ◽  
Vol 17 ◽  
Author(s):  
Sorin Draga ◽  
Laura Olariu ◽  
Speranta Avram
Keyword(s):  
Molecular Dynamics ◽  
Secondary Structure ◽  
Serotonin Transporter ◽  
Structure Prediction ◽  
High Probability ◽  
Secondary Structure Prediction ◽  
Terminal Segment ◽  
Post Translational Modifications ◽  
Structure And Dynamics ◽  
N Terminus

Background: The human serotonin transporter is an important drug target for the treatment of various medical conditions of which depression is the most important, but also include attention deficit hyperactivity disorder, schizophrenia, social anxiety disorder and irritable bowel syndrome, among others. The transmembrane portion of the human transporter has been studied extensively and first crystalized in 2016. However, the dynamical nature of the N-terminal segment of pro-tein and its post-translational modifications remain insufficiently explored. Objective: The present study aims to evaluate the structure and dynamics of the N-terminal segment of the human serotonin transporter and the presence and stability of possible secondary structure elements along with its post-translational modifica-tions and disorder propensity. Methods: The segment was investigated using a combination of bioinformatics tools for physico-chemical characterization, secondary structure prediction, post-translational modifications and disorder prediction, followed by ab initio modeling and microsecond long explicit solvent molecular dynamics. Results: Our study reveals the presence of metastable secondary structure elements, namely two alpha helices and a beta-sheet, throughout the molecular dynamics run and identifies numerous sites with high probability for post-translational mod-ifications. Conclusion: Our results show that, despite the intrinsically unstructured nature, the N-terminus adopts a stable confor-mation with stable secondary structure elements, that could indicate an important functional role for the segment. Also, there is a high probability that the segment undergoes multiple post-translational modifications.

scholarly journals The role of post-translational modifications by ubiquitin/ISG15 tags in exposed proteins during NETosis: Immunogenic or tolerogenic signaling process in Systemic Lupus Erythematosus?

2020 ◽  
Author(s):  
Daniel Alberto Carrillo-Vázquez ◽  
Eduardo Jardón-Valadez. ◽  
Jiram Torres-Ruiz ◽  
Guillermo Juárez-Vega ◽  
José Luis Maravillas-Montero ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Molecular Dynamics ◽  
Lupus Erythematosus ◽  
Hydration Status ◽  
Healthy Controls ◽  
Heme Group ◽  
Systemic Lupus ◽  
Post Translational Modifications ◽  
The Impact

Abstract Background: Neutrophil extracellular traps (NETs) from patients with Systemic Lupus Erythematosus (SLE) are characterized by lower ubiquitylation and myeloperoxidase (MPO) as a substrate. The structural and functional effect of such modification and if there are additional post-translational modifications (PTMs) are unknown.Methods: To assess the expression and functional role of PTMs in NETs of patients with SLE; reactivation, proliferation and cytokine production was evaluated by flow cytometry using co-cultures with dendritic cells (DC) and CD4+ from SLE patients and healthy controls. The impact of ubiquitylation on MPO was assessed by molecular dynamics. The expression of ISG15 in NETs was evaluated by immunofluorescence and Western Blot.Results: Fifteen patients with SLE and 10 healthy controls were included. In the co-cultures of CD4+ lymphocytes with DC stimulated with ubiquitylated MPO or recombinant MPO, a higher expression of IFNγ and IL17A was found in CD4+ from SLE patients (p < 0.05). Furthermore, with DC stimulated with ubiquitylated MPO a trend towards increased expression of CD25 and Ki67 was found in lupus CD4+ lymphocytes, while the opposite was documented in controls (p < 0.05). Through molecular dynamics we found the K129-K488-K505 residues of MPO as susceptible to ubiquitylation. Ubiquitylation affects the hydration status of the HEME group depending on the residue to which it is conjugated. R239 was found near by the HEME group when the ubiquitin was in K488-K505. In addition, we found greater expression of ISG15 in the SLE NETs vs controls (p < 0.05), colocalization with H2B (r = 0.78) only in SLE samples and increased production of IFNγ in PBMCs stimulated with lupus NETs compared to healthy controls NETs.Conclusion: The ubiquitylated MPO has a differential effect on the induction of reactivation and proliferation of CD4+ lymphocytes in patients with SLE, which may be related to structural changes by ubiquitylation at the catalytic site of MPO. Besides a lower ubiquitylation pattern, NETs of patients with SLE are characterized by the expression of H2B conjugated with ISG15, and the induction of IFNγ by Th1 cells.

scholarly journals Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications

2019 ◽  
Vol 20 (5) ◽  
pp. 1252 ◽  
Author(s):  
Pavel Semenyuk ◽  
Vladimir Muronetz
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
Dynamics Simulation ◽  
Unfolded Proteins ◽  
Post Translational Modifications ◽  
Dna And Rna ◽  
Charged Polymers ◽  
Local Charge ◽  
Charged Macromolecules ◽  
Dynamics Simulations

Interaction of proteins with charged macromolecules is involved in many processes in cells. Firstly, there are many naturally occurred charged polymers such as DNA and RNA, polyphosphates, sulfated glycosaminoglycans, etc., as well as pronouncedly charged proteins such as histones or actin. Electrostatic interactions are also important for “generic” proteins, which are not generally considered as polyanions or polycations. Finally, protein behavior can be altered due to post-translational modifications such as phosphorylation, sulfation, and glycation, which change a local charge of the protein region. Herein we review molecular modeling for the investigation of such interactions, from model polyanions and polycations to unfolded proteins. We will show that electrostatic interactions are ubiquitous, and molecular dynamics simulations provide an outstanding opportunity to look inside binding and reveal the contribution of electrostatic interactions. Since a molecular dynamics simulation is only a model, we will comprehensively consider its relationship with the experimental data.

scholarly journals A Systematic Framework for Molecular Dynamics Simulations of Protein Post-Translational Modifications

2013 ◽  
Vol 9 (7) ◽  
pp. e1003154 ◽  
Author(s):  
Drazen Petrov ◽  
Christian Margreitter ◽  
Melanie Grandits ◽  
Chris Oostenbrink ◽  
Bojan Zagrovic
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Post Translational Modifications ◽  
Dynamics Simulations ◽  
Systematic Framework

scholarly journals Oxidative Modified Fibrinogen in Cardiovascular Diseases

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5011-5011
Author(s):  
Jana Štikarová ◽  
Jiri Suttnar ◽  
Zofie Sovova ◽  
Eliska Ceznerova ◽  
Jaromir Novak ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Amino Acids ◽  
Czech Republic ◽  
Cardiovascular Diseases ◽  
Control Group ◽  
Amino Acid Residues ◽  
Post Translational Modifications ◽  
Dynamics Simulations

Abstract Background Cardiovascular diseases are linked with oxidative stress which is the source of reactive oxidative and nitrative species, contributors of post-translational modification. Fibrinogen due to its high concentration in blood is considered as one of the most sought of targets of oxidative stress substances. Post-translational modifications of fibrinogen might influence its physiological function, thus affect hemostasis in the terms of fibrin nets forming and architecture or interaction with platelets. The aim of this study was to observe influence of in vivo fibrinogen modifications on formation of fibrin net and to identify amino acid residues prone to changes related to oxidative stress. Methods Plasma samples were collected from patients of The Military University Hospital Prague in the agreement with ethical committees of participating institutions and with informed consents from all subjects. Samples were divided into 4 groups: patients with acute coronary syndrome (A), patients with stroke (B), patients with thrombus localized in carotid vein (C) and control group (patients without coronary atherosclerosis; D). Fibrin net architecture was studied by scanning electron microscopy (Mira 3 LMH, Tescan Orsay Holding, a.s., Brno, Czech Republic). For identification of modified amino acids residue mass spectroscopy was used (Triple TOF 6600, Sciex). Molecular dynamics simulations of hydrated protein were performed in Gromacs software with Gromos force fields. Crystal structure 3GHG was used as a reference structure to which post-translational modifications were introduced manually in Yasara View. Results We found extensive both qualitative and quantitative changes in the structure of fibrinogen molecule in all groups of patients. Oxidative stress level differed among patient groups and between the control group. Different oxidative changes caused by in vivo modifications of fibrinogen affected quite distinctly the architecture of fibrin net. Modified amino acids were detected in all three fibrinogen chains. In gamma chain the localisation of modified amino acid residues correlated with the part of fibrinogen important for fibrin polymerisation. The impact of the most pronounced post-translational modifications on the secondary structure of fibrinogen was described by molecular dynamics simulations. Conclusions The results show that the degree of impairment of fibrinogen functions in the cardiovascular diseases is related to the level of oxidative stress. Characterization of oxidative fibrinogen modification and its precise meaning to the function of fibrinogen in hemostasis appears to be extremely helpful to better understanding of thrombotic/bleeding complications linked with various cardiovascular diseases. Acknowledgments This work was supported by the Ministry of Health, Czech Republic, no. 00023736, by the Academy of Sciences, Czech Republic no. P205/12/G118 and NV18-08-00149, by ERDF OPPK CZ.2.16/3.1.00/24001 and by the European Regional Development Fund and the state budget of the Czech Republic (project AIIHHP: CZ.02.1.01/0.0/0.0/16_025/0007428, OP RDE, Ministry of Education, Youth and Sports). Disclosures No relevant conflicts of interest to declare.

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