scholarly journals Electrostatics and Solvation: Essential Determinants of Chromatin Compaction

2019 ◽  
Author(s):  
A. Bendandi ◽  
S. Dante ◽  
S. Rehana Zia ◽  
A. Diaspro ◽  
W. Rocchia
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Ionic Concentration ◽  
Coarse Grained ◽  
Chromatin Compaction ◽  
Spatial And Temporal Scales ◽  
Chromatin Fibre ◽  
Nucleosome Core ◽  
Wide Range

ABSTRACTChromatin compaction is a process of fundamental importance in Biology, as it greatly influences cellular function and gene expression. The dynamics of compaction is determined by the interactions between DNA and histones, which are mainly mechanical and electrostatic. The high charge of DNA makes electrostatics extremely important for chromatin topology and dynamics. Besides their mechanical and steric role in the chromatin fibre, linker DNA length and linker histone presence and binding position also bear great electrostatic consequences. Electrostatics in chromatin is also indirectly linked to the DNA sequence: the presence of high-curvature AT-rich segments in DNA can cause conformational variations with electrostatic repercussions, attesting to the fact that the role of DNA is both structural and electrostatic. Electrostatics in this system has been analysed by extensively examining at the computational level the repercussions of varying ionic concentration, using all-atom, coarse-grained, and continuum models. There have been some tentative attempts to describe the force fields governing chromatin conformational changes and the energy landscapes of these transitions, but the intricacy of the system has hampered reaching a consensus. Chromatin compaction is a very complex issue, depending on many factors and spanning orders of magnitude in space and time in its dynamics. Therefore, comparison and complementation of theoretical models with experimental results is fundamental. Here, we present existing approaches to analyse electrostatics in chromatin and the different points of view from which this issue is treated. We pay particular attention to solvation, often overlooked in chromatin studies. We also present some numerical results on the solvation of nucleosome core particles. We discuss experimental techniques that have been combined with computational approaches and present some related experimental data such as the Z-potential of nucleosomes at varying ionic concentrations. Finally, we discuss how these observations support the importance of electrostatics and solvation in chromatin models.SIGNIFICANCEThis work explores the determinants of chromatin compaction, focusing on the importance of electrostatic interactions and solvation. Chromatin compaction is an intrinsically multiscale issue, since processes concerning chromatin occur on a wide range of spatial and temporal scales. Since DNA is a highly charged macromolecule, electrostatic interactions are extremely significant for chromatin compaction, an effect examined in this work from many angles, such as the importance of ionic concentration and different ionic types, DNA-protein interactions, and solvation. Solvation is often overlooked in chromatin studies, especially in coarse-grained models, where the nucleosome core, the building block of the chromatin fibre, is represented as a rigid body, even though it has been observed that solvation influences chromatin even at the base-pair level.

scholarly journals Cofactor-mediated amyloidogenesis

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Jillian Madine
Keyword(s):  
Conformational Change ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Zinc Binding ◽  
Amyloid Protein ◽  
Wide Range ◽  
Pathogenesis Related Protein ◽  
Plant Pathogenesis

Abstract A recent study published in Bioscience Reports by Sheng et al. (Bioscience Reports, (2019) 39, pii:BSR20182345] described a small but significant conformational change that occurs upon zinc binding and results in initiation of the amyloidogenic aggregation cascade of Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) in the presence of heparin. The present study describes a two-stage process that is required for the initiation of the amyloidogenic aggregation cascade involving a concentration step and a conformation change to enhance accessibility of natively protected amyloidogenic regions for self-association. For GAPR-1 in the present study, these steps are provided by zinc binding causing the required conformational change enhancing accessibility of amyloidogenic regions, and heparin providing a template or scaffold in turn increasing the local protein concentration. Cofactors such as glycosaminoglycans and metal ions have been found associated with amyloid deposits in vivo and shown to affect protein assembly kinetics in vitro. Cofactor interactions with the amyloidogenic process are an area of great interest for therapeutic intervention for the wide range of diseases known to be associated with amyloid protein aggregation. The present study emphasises the need for enhanced structural understanding of cofactor–amyloid protein interactions and highlights that small subtle conformational changes can have large impacts on resulting aggregation processes.

scholarly journals Molecular determinants of the interactions between proteins and ssDNA

2015 ◽  
Vol 112 (16) ◽  
pp. 5033-5038 ◽  
Author(s):  
Garima Mishra ◽  
Yaakov Levy
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Binding Pocket ◽  
Dna Bases ◽  
Coarse Grained ◽  
Binding Modes ◽  
Ssdna Binding ◽  
Coarse Grained Model ◽  
Molecular Determinants ◽  
Ssdna Binding Proteins

ssDNA binding proteins (SSBs) protect ssDNA from chemical and enzymatic assault that can derail DNA processing machinery. Complexes between SSBs and ssDNA are often highly stable, but predicting their structures is challenging, mostly because of the inherent flexibility of ssDNA and the geometric and energetic complexity of the interfaces that it forms. Here, we report a newly developed coarse-grained model to predict the structure of SSB–ssDNA complexes. The model is successfully applied to predict the binding modes of six SSBs with ssDNA strands of lengths of 6–65 nt. In addition to charge–charge interactions (which are often central to governing protein interactions with nucleic acids by means of electrostatic complementarity), an essential energetic term to predict SSB–ssDNA complexes is the interactions between aromatic residues and DNA bases. For some systems, flexibility is required from not only the ssDNA but also, the SSB to allow it to undergo conformational changes and the penetration of the ssDNA into its binding pocket. The association mechanisms can be quite varied, and in several cases, they involve the ssDNA sliding along the protein surface. The binding mechanism suggests that coarse-grained models are appropriate to study the motion of SSBs along ssDNA, which is expected to be central to the function carried out by the SSBs.

scholarly journals Molecular Mechanism of Methyl-Dependent and Spatial-Specific DNA Recognition of c-Jun Homodimere

2021 ◽  
Author(s):  
Lihua Bie ◽  
Jun-wen Fei ◽  
Jun Gao
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Regulation Of Gene Expression ◽  
Local Environment ◽  
Small Contribution ◽  
Methyl Group ◽  
Cpg Sites ◽  
Specific Recognition ◽  
Bottom Strand

Abstract DNA methylation is important in regulation of gene expression and normal development because it alters the interplay between protein and DNA. Experiments have shown that a single 5-methylcytosine at different CpG sites (mCpG) might have different effects on specific recognition, but the atomistic origin and dynamic details are largely unclear. In this work, we investigated the mechanism of monomethylation at different CpG sites in the cognate motif and the cooperativity of full methylation. By constructing four models of c-Jun/Jun protein binding to the 5’-XGAGTCA -3’(X represents C or methylated C) motif, we characterized the dynamics of the contact interface using the all-atom molecular dynamics method. Free energy analysis of MM/GBSA suggests that regardless of whether the C12pG13 site of the bottom strand is methylated, the effects from mC25pG26 of the top strand are dominant and can moderately enhance the binding by ~ 31kcal/mol, whereas mC12pG13 showed a relatively small contribution, in agreement with the experimental data. Remarkably, we found that this spatial-specific influence was induced by different regulatory rules. The influence of the mC25pG26 site is mainly mediated by steric hindrance. The additional methyl group leads to the conformational changes in nearby residues and triggers an obvious structural bending in the protein, which results in the formation of a new T-ASN-C triad that enhances the specific recognition of TCA half-sites. The substitution of the methyl group at the C12pG13 site of the bottom strand breaks the original H-bonds directly. Such changes in electrostatic interactions also lead to the remote allosteric effects of protein by multifaceted interactions but have negligible contributions to binding. Although these two influence modes are different, they can both fine-tune the local environment, which might produce remote allosteric effects through protein-protein interactions. Further analysis reveals that the discrepancies in these two modes are primarily due to their location. Moreover, when both sites are methylated, the major determinant of binding specificity depends on the context and the location of the methylation site, which is the result of crosstalk and cooperativity.

Structure of the regulatory complex of Escherichia coli IIIGlc with glycerol kinase

Science ◽  
1993 ◽  
Vol 259 (5095) ◽  
pp. 673-677 ◽  
Author(s):  
JH Hurley ◽  
HR Faber ◽  
D Worthylake ◽  
ND Meadow ◽  
S Roseman ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Phosphorylation Site ◽  
Adenosine Diphosphate ◽  
Glycerol Kinase ◽  
Transport Systems ◽  
Protein Protein Interactions ◽  
Binding Domains ◽  
Regulatory Complex

The phosphocarrier protein IIIGlc is an integral component of the bacterial phosphotransferase (PTS) system. Unphosphorylated IIIGlc inhibits non-PTS carbohydrate transport systems by binding to diverse target proteins. The crystal structure at 2.6 A resolution of one of the targets, glycerol kinase (GK), in complex with unphosphorylated IIIGlc, glycerol, and adenosine diphosphate was determined. GK contains a region that is topologically identical to the adenosine triphosphate binding domains of hexokinase, the 70-kD heat shock cognate, and actin. IIIGlc binds far from the catalytic site of GK, indicating that long-range conformational changes mediate the inhibition of GK by IIIGlc. GK and IIIGlc are bound by hydrophobic and electrostatic interactions, with only one hydrogen bond involving an uncharged group. The phosphorylation site of IIIGlc, His90, is buried in a hydrophobic environment formed by the active site region of IIIGlc and a 3(10) helix of GK, suggesting that phosphorylation prevents IIIGlc binding to GK by directly disrupting protein-protein interactions.

scholarly journals Harnessing protein folding neural networks for peptide–protein docking

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Tomer Tsaban ◽  
Julia K. Varga ◽  
Orly Avraham ◽  
Ziv Ben-Aharon ◽  
Alisa Khramushin ◽  
...  
Keyword(s):  
Neural Networks ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Protein Docking ◽  
Great Promise ◽  
Learning Approaches ◽  
Multiple Sequence ◽  
Starting Point ◽  
Wide Range

AbstractHighly accurate protein structure predictions by deep neural networks such as AlphaFold2 and RoseTTAFold have tremendous impact on structural biology and beyond. Here, we show that, although these deep learning approaches have originally been developed for the in silico folding of protein monomers, AlphaFold2 also enables quick and accurate modeling of peptide–protein interactions. Our simple implementation of AlphaFold2 generates peptide–protein complex models without requiring multiple sequence alignment information for the peptide partner, and can handle binding-induced conformational changes of the receptor. We explore what AlphaFold2 has memorized and learned, and describe specific examples that highlight differences compared to state-of-the-art peptide docking protocol PIPER-FlexPepDock. These results show that AlphaFold2 holds great promise for providing structural insight into a wide range of peptide–protein complexes, serving as a starting point for the detailed characterization and manipulation of these interactions.

scholarly journals Cooperation within von Willebrand factors enhances adsorption mechanism

2015 ◽  
Vol 12 (109) ◽  
pp. 20150334 ◽  
Author(s):  
Maziar Heidari ◽  
Mehrdad Mehrbod ◽  
Mohammad Reza Ejtehadi ◽  
Mohammad R. K. Mofrad
Keyword(s):  
Conformational Changes ◽  
Van Der Waals Interactions ◽  
Coarse Grained ◽  
Collagen Fibres ◽  
Receptor Field ◽  
Adsorption Dynamics ◽  
Shear Rates ◽  
Collagen Receptors ◽  
Wide Range ◽  
Von Willebrand

von Willebrand factor (VWF) is a naturally collapsed protein that participates in primary haemostasis and coagulation events. The clotting process is triggered by the adsorption and conformational changes of the plasma VWFs localized to the collagen fibres found near the site of injury. We develop coarse-grained models to simulate the adsorption dynamics of VWF flowing near the adhesive collagen fibres at different shear rates and investigate the effect of factors such as interaction and cooperativity of VWFs on the success of adsorption events. The adsorption probability of a flowing VWF confined to the receptor field is enhanced when it encounters an adhered VWF in proximity to the collagen receptors. This enhancement is observed within a wide range of shear rates and is mostly controlled by the attractive van der Waals interactions rather than the hydrodynamic interactions among VWF monomers. The cooperativity between the VWFs acts as an effective mechanism for enhancing VWF adsorption to the collagen fibres. Additionally, this implies that the adsorption of such molecules is nonlinearly dependent on the density of flowing VWFs. These findings are important for studies of primary haemostasis as well as general adsorption dynamics processes in polymer physics.

Reducing full-field training data to time series

2021 ◽  
Author(s):  
Wouter Edeling ◽  
Daan Crommelin
Keyword(s):  
Time Series ◽  
Surrogate Model ◽  
Ocean Model ◽  
Training Data ◽  
Data Driven ◽  
Coarse Grained ◽  
Full Field ◽  
Spatial And Temporal Scales ◽  
Wide Range ◽  
Quantities Of Interest

<p>It is well known that the wide range of spatial and temporal scales present in geophysical flow problems represents a (currently) insurmountable computational bottleneck, which must be circumvented by a coarse-graining procedure. The effect of the unresolved fluid motions enters the coarse-grained equations as an unclosed forcing term, denoted as the ’eddy forcing’. Traditionally, the system is closed by approximate deterministic closure models, i.e. so-called parameterizations. Instead of creating a deterministic parameterization, some recent efforts have focused on creating a stochastic, data-driven surrogate model for the eddy forcing from a (limited) set of reference data, with the goal of accurately capturing the long-term flow statistics. Since the eddy forcing is a dynamically evolving field, a surrogate should be able to mimic the complex spatial patterns displayed by the eddy forcing. Rather than creating such a (fully data-driven) surrogate, we propose to precede the surrogate construction step by a procedure that replaces the eddy forcing with a new source term which: i) is tailor-made to capture spatially-integrated quantities of interest, ii) strikes a balance between physical insight and data-driven modelling , and iii) significantly reduces the amount of training data that is needed. Instead of creating a surrogate model for an evolving field, we now only require a surrogate model for one scalar time series per quantity-of-interest. We derive the new source terms for a simplified an ocean model of two-dimensional turbulence in a doubly periodic square domain, and show that the time-series training data produces the same statistics for our quantities of interest as the full-field eddy-forcing.</p>

scholarly journals Emergence of ion channel modal gating from independent subunit kinetics

2016 ◽  
Vol 113 (36) ◽  
pp. E5288-E5297 ◽  
Author(s):  
Brendan A. Bicknell ◽  
Geoffrey J. Goodhill
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Ionic Currents ◽  
Analytical Framework ◽  
Stochastic Simulations ◽  
Coarse Grained ◽  
Wide Range ◽  
Intracellular Ca ◽  
Modal Gating ◽  
Kinetics Of

Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

scholarly journals Elucidation of ion effects on the Thermodynamics of RNA Folding

2018 ◽  
Author(s):  
Natalia A. Denesyuk ◽  
D. Thirumalai
Keyword(s):  
Free Energy ◽  
Single Molecule ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Rna Folding ◽  
Coarse Grained ◽  
Significant Advance ◽  
Rna Molecules ◽  
Ion Effects ◽  
The Difference

AbstractHow ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free energy change, ΔG(c), of RNA upon folding varies with the salt concentration (c) as, ΔG(c) = kc ln c + const, where the coefficient kc is proportional to the difference in the uptake of ions (ion preferential coefficient), ΔΓ, between the folded and unfolded states. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between folding free energy and ion preferential coefficient. Without any input from experiments, the simulations quantitatively reproduce the heat capacity for the −1 frame shifting pseudoknot (PK) from Beet Western Yellow Virus, thus validating the model. We show that ΔG(c) calculated directly from ΔΓ varies linearly with ln c (c < 0.2M), for a hairpin and the PK, thus demonstrating a molecular link between the two quantities for RNA molecules that undergo substantial conformational changes during folding. Explicit ion simulations also show the linear dependence of ΔG(c) on ln c at all c with kc = 2kBT, except that ΔG(c) values are shifted by about 2 kcal/mol higher than experiments at all salt concentrations. The discrepancy is due to an underestimate the Γ values for both the folded and unfolded states, while giving accurate values for ΔΓ. The predictions for the salt dependence of ΔΓ are amenable to test using single molecule pulling experiments. Our simulations, representing a significant advance in quantitatively describing ion effects in RNA, show that the framework provided here can be used to obtain accurate thermodynamics of RNA folding.

Patterns in diversity and composition of the microbenthos of subarctic intertidal beaches with different morphodynamics

2020 ◽  
Vol 648 ◽  
pp. 19-38
Author(s):  
AI Azovsky ◽  
YA Mazei ◽  
MA Saburova ◽  
PV Sapozhnikov
Keyword(s):  
Species Abundance ◽  
Abundance Ratio ◽  
Wave Action ◽  
Coarse Grained ◽  
Sediment Properties ◽  
Β Diversity ◽  
Α Diversity ◽  
Wide Range ◽  
Similar Mode ◽  
Abundance And Diversity

Diversity and composition of benthic diatom algae and ciliates were studied at several beaches along the White and Barents seas: from highly exposed, reflective beaches with coarse-grained sands to sheltered, dissipative silty-sandy flats. For diatoms, the epipelic to epipsammic species abundance ratio was significantly correlated with the beach index and mean particle size, while neither α-diversity measures nor mean cell length were related to beach properties. In contrast, most of the characteristics of ciliate assemblages (diversity, total abundance and biomass, mean individual weight and percentage of karyorelictids) demonstrated a strong correlation to beach properties, remaining low at exposed beaches but increasing sharply in more sheltered conditions. β-diversity did not correlate with beach properties for either diatoms or ciliates. We suggest that wave action and sediment properties are the main drivers controlling the diversity and composition of the intertidal microbenthos. Diatoms and ciliates, however, demonstrated divergent response to these factors. Epipelic and epipsammic diatoms exhibited 2 different strategies to adapt to their environments and therefore were complementarily distributed along the environmental gradient and compensated for each other in diversity. Most ciliates demonstrated a similar mode of habitat selection but differed in their degree of tolerance. Euryporal (including mesoporal) species were relatively tolerant to wave action and therefore occurred under a wide range of beach conditions, though their abundance and diversity were highest in fine, relatively stable sediments on sheltered beaches, whereas the specific interstitial (i.e. genuine microporal) species were mostly restricted to only these habitats.

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