scholarly journals Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

2018 ◽  
Author(s):  
Giovanni B. Brandani ◽  
Shoji Takada
Keyword(s):  
Genome Organization ◽  
Electrostatic Interactions ◽  
Defect Formation ◽  
Energy Landscape ◽  
Molecular Machines ◽  
Biological Processes ◽  
Complete Understanding ◽  
Chromatin Remodelers ◽  
Nucleosomal Dna ◽  
Dynamics Simulations

ABSTRACTATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the remodeler overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA unidirectionally. The sliding is initiated at the remodeler binding location via the generation of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning, explaining several past experimental observations. These results offer a detailed mechanistic picture of remodeling important for the complete understanding of these important biological processes.

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 Characterization of design grammar of peptides for regulating liquid droplets and aggregates of FUS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyoto Kamagata ◽  
Rika Chiba ◽  
Ichiro Kawahata ◽  
Nanako Iwaki ◽  
Saori Kanbayashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
Droplet Formation ◽  
Liquid Droplets ◽  
Proof Of Concept ◽  
Aggregate Formation ◽  
Fused In Sarcoma ◽  
Dynamics Simulations

AbstractLiquid droplets of aggregation-prone proteins, which become hydrogels or form amyloid fibrils, are a potential target for drug discovery. In this study, we proposed an experiment-guided protocol for characterizing the design grammar of peptides that can regulate droplet formation and aggregation. The protocol essentially involves investigation of 19 amino acid additives and polymerization of the identified amino acids. As a proof of concept, we applied this protocol to fused in sarcoma (FUS). First, we evaluated 19 amino acid additives for an FUS solution and identified Arg and Tyr as suppressors of droplet formation. Molecular dynamics simulations suggested that the Arg additive interacts with specific residues of FUS, thereby inhibiting the cation–π and electrostatic interactions between the FUS molecules. Second, we observed that Arg polymers promote FUS droplet formation, unlike Arg monomers, by bridging the FUS molecules. Third, we found that the Arg additive suppressed solid aggregate formation of FUS, while Arg polymer enhanced it. Finally, we observed that amyloid-forming peptides induced the conversion of FUS droplets to solid aggregates of FUS. The developed protocol could be used for the primary design of peptides controlling liquid droplets and aggregates of proteins.

scholarly journals Spatial segregation of mixed-sized counterions in dendritic polyelectrolytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. S. Kłos ◽  
J. Paturej
Keyword(s):  
Electrostatic Interactions ◽  
Spatial Separation ◽  
Excluded Volume ◽  
The Core ◽  
Bjerrum Length ◽  
Two Component ◽  
Conformational Properties ◽  
Dynamics Simulations ◽  
Two Parameters ◽  
Swelling Factor

AbstractLangevin dynamics simulations are utilized to study the structure of a dendritic polyelectrolyte embedded in two component mixtures comprised of conventional (small) and bulky counterions. We vary two parameters that trigger conformational properties of the dendrimer: the reduced Bjerrum length, $$\lambda _B^*$$ λ B ∗ , which controls the strength of electrostatic interactions and the number fraction of the bulky counterions, $$f_b$$ f b , which impacts on their steric repulsion. We find that the interplay between the electrostatic and the counterion excluded volume interactions affects the swelling behavior of the molecule. As compared to its neutral counterpart, for weak electrostatic couplings the charged dendrimer exists in swollen conformations whose size remains unaffected by $$f_b$$ f b . For intermediate couplings, the absorption of counterions into the pervaded volume of the dendrimer starts to influence its conformation. Here, the swelling factor exhibits a maximum which can be shifted by increasing $$f_b$$ f b . For strong electrostatic couplings the dendrimer deswells correspondingly to $$f_b$$ f b . In this regime a spatial separation of the counterions into core–shell microstructures is observed. The core of the dendrimer cage is preferentially occupied by the conventional ions, whereas its periphery contains the bulky counterions.

Computational studies of ice defects

2003 ◽  
Vol 81 (1-2) ◽  
pp. 325-332 ◽  
Author(s):  
P LM Plummer
Keyword(s):  
Defect Formation ◽  
Structural Evolution ◽  
Energy Difference ◽  
Electronic Energy ◽  
Energy Structure ◽  
Defect Site ◽  
And Migration ◽  
Dynamics Simulations ◽  
Small Clusters ◽  
Structure Calculations

Continuing our investigations of the energetics associated with defect formation and migration, both ab initio energy-structure calculations and molecular dynamics simulations are carried out on small clusters of water molecules containing one or more defects in hydrogen bonding. Previous studies in this series have identified structures containing defects that are stable at 0 K or that are transition states between such structures. However, results from this laboratory and elsewhere have shown that the energy required for the production or migration of a defect is more complex than merely the energy difference between the static structures. Cooperative motion of neighbors to the defect site can either increase or decrease the energy involved to produce or annihilate the defect. Thus, experimental measurements associated with the energy of defects in ice can differ substantially from those calculated using static models. By increasing the complexity of the model, the studies described in this report attempt to more realistically simulate a defect-containing ice system. The types of defects studied include ion and ion-pair defects. The initial structures are energetically stable — minima on the electronic energy surface — and contain one or more kinds of defects. Since the means and amount of energy injection can alter the migration path, the energy is introduced into the system in a variety of ways. The structural evolution of the ice system is then monitored as a function of time. PACS Nos.: 82.20Wt, 82.20Kh, 82.30Rs

scholarly journals Function of cofactor Akirin2 in the regulation of gene expression in model human Caucasian neutrophil-like HL60 cells

2021 ◽  
Author(s):  
Sara Artigas-Jerónimo ◽  
Margarita Villar ◽  
Agustín Estrada-Peña ◽  
Adrián Velázquez-Campoy ◽  
Pilar Alberdi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Development ◽  
Transcriptional Activation ◽  
Regulation Of Gene Expression ◽  
Regulatory Function ◽  
Biological Processes ◽  
Protein Targets ◽  
Chromatin Remodelers ◽  
Hl60 Cells ◽  
Associated Proteins

The Akirin family of transcription cofactors are involved throughout the metazoan in the regulation of different biological processes such as immunity, interdigital regression, muscle and neural development. Akirin do not have catalytic or DNA-binding capability and exert its regulatory function primarily through interacting proteins such as transcription factors, chromatin remodelers, and RNA-associated proteins. In this study, we focused on the human Akirin2 regulome and interactome in neutrophil-like model human Caucasian promyelocytic leukemia HL60 cells. Our hypothesis is that metazoan evolved to have Akirin2 functional complements and different Akirin2-mediated mechanisms for the regulation of gene expression. To address this hypothesis, experiments were conducted using transcriptomics, proteomics and systems biology approaches in akirin2 knockdown and wildtype HL60 cells to characterize Akirin2 gene/protein targets, functional complements and to provide evidence of different mechanisms that may be involved in Akirin2-mediated regulation of gene expression. The results revealed Akirin2 gene/protein targets in multiple biological processes with higher representation of immunity and identified immune response genes as candidate Akirin2 functional complements. In addition to linking chromatin remodelers with transcriptional activation, Akirin2 also interacts with histone H3.1 for regulation of gene expression.

scholarly journals DNA methylation cues in nucleosome geometry, stability, and unwrapping

2021 ◽  
Author(s):  
Shuxiang Li ◽  
Yunhui Peng ◽  
David Landsman ◽  
Anna Panchenko
Keyword(s):  
Conformational Changes ◽  
Cytosine Methylation ◽  
Epigenetic Mark ◽  
Nucleosome Assembly ◽  
Functional Studies ◽  
Nucleosome Dynamics ◽  
Nucleosomal Dna ◽  
Dna Unwrapping ◽  
Dynamics Simulations ◽  
Eukaryotic Organisms

Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported in both prokaryotes and eukaryotes, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here we investigated the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations (five microsecond long trajectories, 60 microseconds in total), we generated extensive atomic level conformational full nucleosome ensembles. Our results revealed that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, shifting the population equilibrium of sugar-phosphate backbone geometry. These conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3-4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microsecond time scale.

Catalysis with a Skip: Dynamically Coupled Addition, Proton Transfer, and Elimination During Au- and Pd-Catalyzed Diol Cyclization

2021 ◽  
Author(s):  
Matthew Teynor ◽  
Windsor Scott ◽  
Daniel Ess
Keyword(s):  
Potential Energy ◽  
Proton Transfer ◽  
Energy Landscape ◽  
Cyclization Reactions ◽  
Potential Energy Landscape ◽  
Water Elimination ◽  
Catalytic Intermediates ◽  
Pd Complexes ◽  
Dynamics Simulations ◽  
Step Mechanism

Au and Pd complexes have emerged as highly effective π-bond cyclization catalysts to construct heterocycles. These cyclization reactions are generally proposed to proceed through multi-step addition-elimination mechanisms involving Au- or Pd-alkyl intermediates. For Au- and Pd-catalyzed allylic diol cyclization, while the DFT potential energy surface landscapes show a stepwise sequence of alkoxylation π-addition, proton transfer, and water elimination, quasiclassical direct dynamics simulations reveal new dynamical mechanisms that depend on the metal center. For Au, trajectories reveal that after π-addition the Au-alkyl intermediate is always skipped because addition is dynamically coupled with proton transfer and water elimination. In contrast, for Pd catalysis, due to differences in the potential-energy landscape shape, only about half of trajectories show Pd-alkyl intermediate skipping. The other half of the trajectories show the traditional two-step mechanism with the intervening Pd-alkyl intermediate. Overall, this work reveals that interpretation of a DFT potential-energy landscape can be insufficient to understand catalytic intermediates and mechanisms and that atomic momenta through dynamics simulations is needed to determine if an intermediate is genuinely part of a catalytic cycle.<br>

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

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