scholarly journals Recognition of N6-methyladenosine by the YTHDC1 YTH domain studied by molecular dynamics and NMR spectroscopy: The role of hydration

2021 ◽  
Author(s):  
Miroslav Krepl ◽  
Fred Franz Damberger ◽  
Christine von Schroetter ◽  
Dominik Theler ◽  
Pavlína Pokorná ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Binding Pocket ◽  
Bulk Water ◽  
Titration Calorimetry ◽  
Water Molecules ◽  
Water Network ◽  
Solvent Interactions ◽  
Yth Domain ◽  
The Cost

AbstractBackgroundThe YTH domain of YTHDC1 belongs to a class of protein “readers”, recognizing the N6-methyladenosine (m6A) chemical modification in mRNA. Static ensemble-averaged structures revealed details of N6-methyl recognition via a conserved aromatic cage.MethodsWe performed molecular dynamics (MD) simulations along with nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) measurements to examine how dynamics and solvent interactions contribute to the m6A recognition and negative selectivity towards unmethylated substrate.ResultsAn intricate network of water-mediated interactions surrounds bound m6A. The unmethylated adenosine allows disruptive intrusions of bulk water deep into the binding pocket, increasing selectivity for m6A. We furthermore show that the YTHDC1’s preference for the 5′-Gm6A-3′ motif is partially facilitated by a network of water-mediated interactions between the 2-amino group of the preceding guanosine and residues deep in the m6A binding pocket. The 5′-Im6A-3′ (where I is inosine) motif can be recognized as well at the cost of disrupting the water network and a small decrease in affinity. The YTHDC1 D479A mutant, which interrupts the water network, also destabilizes m6A binding. Lastly, we formulate and test an easy-to-implement approach for increasing the agreement between simulations and NMR experiments by using the HBfix potential function for stabilization of key NOE distances. We call the new approach NOEfix.ConclusionsThe structured water molecules surrounding the bound RNA and the methylated substrate’s ability to exclude bulk water molecules are important elements of the YTH domain’s preference for m6A. Network of water molecules also fine tunes the specificity towards 5′-Gm6A-3′ motifs.General SignificanceOur interdisciplinary study of YTHDC1 protein/RNA complex reveals an unusual mechanism by which solvent dynamics can contribute towards recognition of methylation by proteins.

scholarly journals Effect of Size and Temperature on Water Dynamics inside Carbon Nano-Tubes Studied by Molecular Dynamics Simulation

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6175
Author(s):  
Amit Srivastava ◽  
Jamal Hassan ◽  
Dirar Homouz
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Underlying Mechanism ◽  
Bulk Water ◽  
Water Dynamics ◽  
Dynamics Simulation ◽  
Water Molecules ◽  
Wide Range ◽  
Carbon Nano Tubes ◽  
20 Nm

Water transport inside carbon nano-tubes (CNTs) has attracted considerable attention due to its nano-fluidic properties, its importance in nonporous systems, and the wide range of applications in membrane desalination and biological medicine. Recent studies show an enhancement of water diffusion inside nano-channels depending on the size of the nano-confinement. However, the underlying mechanism of this enhancement is not well understood yet. In this study, we performed Molecular Dynamics (MD) simulations to study water flow inside CNT systems. The length of CNTs considered in this study is 20 nm, but their diameters vary from 1 to 10 nm. The simulations are conducted at temperatures ranging from 260 K to 320 K. We observe that water molecules are arranged into coaxial water tubular sheets. The number of these tubular sheets depends on the CNT size. Further analysis reveals that the diffusion of water molecules along the CNT axis deviates from the Arrhenius temperature dependence. The non-Arrhenius relationship results from a fragile liquid-like water component persisting at low temperatures with fragility higher than that of the bulk water.

scholarly journals Molecular Dynamics Modellization and Simulation of Water Diffusion through Plant Cutin

1999 ◽  
Vol 54 (11) ◽  
pp. 896-902 ◽  
Author(s):  
Antonio Matas ◽  
Antonio Heredia
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Structural Information ◽  
Md Simulations ◽  
Water Molecules ◽  
Plant Cuticle ◽  
X Ray Diffraction ◽  
Cross Link ◽  
X Ray ◽  
Good Agreement

Abstract A theoretical molecular modelling study has been conducted for cutin, the biopolyester that forms the main structural component of the plant cuticle. Molecular dynamics (MD) simulations, extended over several ten picoseconds, suggests that cutin is a moderately flexible netting with motional constraints mainly located at the cross-link sites of functional ester groups. This study also gives structural information essentially in accordance with previously reported experimental data, obtained from X -ray diffraction and nuclear magnetic resonance experiments. MD calculations were also performed to simulate the diffusion of water mole­cules through the cutin biopolymer. The theoretical analysis gives evidence that water perme­ation proceedes by a “hopping mechanism”. Coefficients for the diffusion of the water molecules in cutin were obtained from their mean-square displacements yielding values in good agreement with experimental data.

scholarly journals Effects of Hydrogen Bonding on the Rotational Dynamics of Water-Like Molecules in Liquids: Insights from Molecular Dynamics Simulations

2020 ◽  
Vol 73 (8) ◽  
pp. 734
Author(s):  
W. A. Monika Madhavi ◽  
Samantha Weerasinghe ◽  
Konstantin I. Momot
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Hydrogen Sulfide ◽  
Spin Relaxation ◽  
Rotational Diffusion ◽  
Molecular Geometry ◽  
Md Simulations ◽  
Water Molecules ◽  
Molecular Reorientation ◽  
Nmr Spin Relaxation

Rotational motion of molecules plays an important role in determining NMR spin relaxation properties of liquids. The textbook theory of NMR spin relaxation predominantly uses the assumption that the reorientational dynamics of molecules is described by a continuous time rotational diffusion random walk with a single rotational diffusion coefficient. Previously we and others have shown that reorientation of water molecules on the timescales of picoseconds is not consistent with the Debye rotational-diffusion model. In particular, multiple timescales of molecular reorientation were observed in liquid water. This was attributed to the hydrogen bonding network in water and the consequent presence of collective rearrangements of the molecular network. In order to better understand the origins of the complex reorientational behaviour of water molecules, we carried out molecular dynamics (MD) simulations of a liquid that has a similar molecular geometry to water but does not form hydrogen bonds: hydrogen sulfide. These simulations were carried out at T=208K and p=1 atm (~5K below the boiling point). Ensemble-averaged Legendre polynomial functions of hydrogen sulfide exhibited a Gaussian decay on the sub-picosecond timescale but, unlike water, did not exhibit oscillatory behaviour. We attribute these differences to hydrogen sulfide’s absence of hydrogen bonding.

scholarly journals Thermodynamics of semi-specific ligand recognition: the binding of dipeptides to the E.coli dipeptide binding protein DppA

2021 ◽  
Author(s):  
Mohamad K. M. Zainol ◽  
Robert J. C. Linforth ◽  
Donald J. Winzor ◽  
David J. Scott
Keyword(s):  
Hydrophobic Interactions ◽  
Chemical Reactivity ◽  
Water Structure ◽  
Binding Pocket ◽  
Titration Calorimetry ◽  
Water Molecules ◽  
Aqueous Environment ◽  
Arginine Residues ◽  
Structure Flexibility

AbstractThis investigation of the temperature dependence of DppA interactions with a subset of three dipeptides (AA. AF and FA) by isothermal titration calorimetry has revealed the negative heat capacity ($$\Delta {C}_{p}^{o}$$ Δ C p o ) that is a characteristic of hydrophobic interactions. The observation of enthalpy–entropy compensation is interpreted in terms of the increased structuring of water molecules trapped in a hydrophobic environment, the enthalpic energy gain from which is automatically countered by the entropy decrease associated with consequent loss of water structure flexibility. Specificity for dipeptides stems from appropriate spacing of designated DppA aspartate and arginine residues for electrostatic interaction with the terminal amino and carboxyl groups of a dipeptide, after which the binding pocket closes to become completely isolated from the aqueous environment. Any differences in chemical reactivity of the dipeptide sidechains are thereby modulated by their occurrence in a hydrophobic environment where changes in the structural state of entrapped water molecules give rise to the phenomenon of enthalpy–entropy compensation. The consequent minimization of differences in the value of ΔG0 for all DppA–dipeptide interactions thus provides thermodynamic insight into the biological role of DppA as a transporter of all dipeptides across the periplasmic membrane.

Stabilization of DPPC lipid bilayers in the presence of co-solutes: molecular mechanisms and interaction patterns

2021 ◽  
Author(s):  
Fabian Keller ◽  
Andreas Heuer ◽  
Hans-Joachim Galla ◽  
Jens Smiatek
Keyword(s):  
Molecular Dynamics ◽  
Density Functional Theory ◽  
Lipid Bilayers ◽  
Density Functional ◽  
Molecular Mechanisms ◽  
Md Simulations ◽  
Water Molecules ◽  
Interaction Patterns ◽  
Conceptual Density Functional Theory ◽  
Functional Theory

The interactions between DPPC lipid bilayers in different phases with ectoine, amino ectoine and water molecules are studied by means of atomistic molecular dynamics (MD) simulations and conceptual density functional theory (DFT) calculations.

scholarly journals Kinesin motility is driven by subdomain dynamics

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wonmuk Hwang ◽  
Matthew J Lang ◽  
Martin Karplus
Keyword(s):  
Molecular Dynamics ◽  
Atpase Activity ◽  
Binding Pocket ◽  
Water Molecules ◽  
The Core ◽  
Hydrolysis Products ◽  
Atomic Mechanism ◽  
Cellular Environment ◽  
Dynamics Simulations ◽  
Motility Cycle

The microtubule (MT)-associated motor protein kinesin utilizes its conserved ATPase head to achieve diverse motility characteristics. Despite considerable knowledge about how its ATPase activity and MT binding are coupled to the motility cycle, the atomic mechanism of the core events remain to be found. To obtain insights into the mechanism, we performed 38.5 microseconds of all-atom molecular dynamics simulations of kinesin-MT complexes in different nucleotide states. Local subdomain dynamics were found to be essential for nucleotide processing. Catalytic water molecules are dynamically organized by the switch domains of the nucleotide binding pocket while ATP is torsionally strained. Hydrolysis products are 'pulled' by switch-I, and a new ATP is 'captured' by a concerted motion of the α0/L5/switch-I trio. The dynamic and wet kinesin-MT interface is tuned for rapid interactions while maintaining specificity. The proposed mechanism provides the flexibility necessary for walking in the crowded cellular environment.

scholarly journals Gating Mechanism of Hv1 Studied by Molecular Dynamic Simulations

2020 ◽  
Vol 4 (1) ◽  
pp. 20
Author(s):  
Thi Tuong Vy Phan
Keyword(s):  
Molecular Dynamics ◽  
Cancer Progression ◽  
Md Simulations ◽  
Proton Channel ◽  
Water Molecules ◽  
State Structure ◽  
Ph Homeostasis ◽  
Dynamic Simulations ◽  
Closed State ◽  
Gating Mechanism

The voltage-gated proton channel (Hv1) plays the important role in proton extrusion, pH homeostasis, sperm motility, and cancer progression. The closed-state structure of Hv1 was recently revealed by X-ray crystallography. However, the opened-state structure has not been captured yet. To investigate the mechanism of proton transfer in Hv1, molecular dynamics (MD) simulations were performed with the closed-state structure of Hv1 under electric field and pH conditions. The residues arrangement on the closed-state structure revealed that the selectivity filter (Asp108) which is located in the hydrophobic layer (consists of two Phe residues 146 and 179) might prevent water penetration. In molecular dynamics simulations, we observed that the channel opened by moving 3 Arg up on the S4 helix and a continuous hydrogen-bonded chain of water molecules (a “water wire”) went through the channel when it opened. During simulations, the open channel allowed water molecules to pass through the channel but excluded other ions. This indicates the Hv1 channel is highly selective for protons. Our results clearly showed the Hv1 channel is voltage-and pH-gradient sensing.

scholarly journals Receptor flexibility in molecular cross-docking

2016 ◽  
Author(s):  
Lucia Sessa ◽  
Luigi Di BIasi ◽  
Rosaura Parisi ◽  
Simona Concilio ◽  
Stefano Piotto
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Ligand Binding ◽  
Computational Cost ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Flexibility ◽  
Cross Docking ◽  
Internal Cavities ◽  
The Cross

Motivation Molecular docking is an efficient method to predict the conformations adopted by the ligand within the target binding site. Usually, standard docking protocol involves only one structure to represent the receptor, overlooking the changes in the binding pocket geometry induced by ligand binding. In our previous work, we observed that different conformations of the same target show different volume and shape of the internal cavities (Sessa et al., 2016). Different ligands may stabilize different receptor conformations with different internal cavities. Consequently, the crystallographic data represent the adaptation of a protein to a particular ligand. Cross-docking is a validation procedure consisting in docking a series of ligands into different conformation of the same receptor. Since the structures of the same receptor can be rather different, the cross-docking analyses are typically very poor. In these cases the internal cavity of the buried binding pocket does not have space enough to accommodate all ligands and this can radically affect the outcome and alter the cross-docking results. The changes of the cavity volume might explain the failure of traditional docking method and support the hypothesis that a single representative structure for the receptor is not enough. Keeping target proteins flexible during the docking has a high computational cost. To overcome this limit, our docking strategy is to represent receptor flexibility through an inexpensive method that generates a series of target structures. Starting from a known target structure, we used the molecular dynamics (MD) simulations to explore the conformational changes induced by ligand binding and to collect several snapshots of receptor structures to perform the cross-docking studies. To validate the accuracy of our flexible protocol in docking, we used a set of 10 crystallographic conformations of Androgen Receptor with the same target but with a different ligand. We performed two parallel experiments of docking, one with a rigid protein target and one considering flexible receptor structures. In addition, we compared the results for both experiments in the re-docking and in the cross-docking analysis. Methods Ten receptor structures complexed with a ligand were extracted from the X-ray structures in the PDB database (Berman et al., 2000). Several conformations for each receptor were selected from the molecular dynamics simulations (MD) at regular time intervals (each 500 ps). The MD simulations were performed with the software YASARA Structure 16.2.14 (Krieger & Vriend, 2014) using AMBER14 as force field. The molecular docking simulations were performed using VINA provided in the YASARA package. "Abstract truncated at 3,000 characters - the full version is available in the pdf file"

scholarly journals Polarizable force field for molecular dynamics simulations of silver nanoparticles

2019 ◽  
Keyword(s):  
Molecular Dynamics ◽  
Polarization Effect ◽  
Md Simulations ◽  
Water Molecules ◽  
Interfacial Water ◽  
Silver Surface ◽  
Polarizable Force Field ◽  
Rod Model ◽  
Adsorption Of Water ◽  
Rigid Rod

Contact of silver metal surfaces with water, ions and organic ligands experiences induced charges, leading to attractive polarization. These forces play an important role at inorganic/organic interfaces and complement other non-bonded surface interactions. Despite the importance of these interactions, it, however, remains difficult to implement polarization effects to classical molecular dynamics (MD) simulations. In this contribution, we first present an overview of two popular polarizable models, such as Drude oscillator and the rigid rod model, which are utilized to mimic the polarizability of bulk metals. Second, we implemented the rigid rod model to the polarizable force field (FF) for a silver atom, which was further adapted for atomistic MD simulations of silver nanoparticles (AgNPs) composed of 1397 atoms. In our model, induced charge polarization is represented by the displacement of a charge-carrying virtual site attached rigidly to an original Ag atom. To explore the role of polarization, we compared the performance of the classical nonpolarizable FF and the new polarizable model in the MD simulations of adsorption of water and ions onto quasi-spherical AgNP and the flat crystalline silver surface. The analysis of the radial distribution function of Ag-Ag atoms demonstrated that the introduction of the polarization effect had minor effects on face-centered cubic (fcc) packing of silver atoms of bare and water-solvated AgNPs. We found that the polarizable FF causes some increase in attractive interactions between the silver surface and water molecules and Na+ ions. As a crucial test of the developed polarizable model, the structure of adsorbed interfacial water molecules was analyzed. Our data suggest that the environment-induced polarization of the silver surface contributes significantly to the structure of adsorbed interfacial water layers and it also plays an important role in the adsorption of positive ions. However, it was also found out that the polarization effect has a rather short-range effect, so that a minor contribution of silver polarization was seen for adsorption of water molecules and ions from distant solvation shells.

scholarly journals Receptor flexibility in molecular cross-docking

2016 ◽  
Author(s):  
Lucia Sessa ◽  
Luigi Di BIasi ◽  
Rosaura Parisi ◽  
Simona Concilio ◽  
Stefano Piotto
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Ligand Binding ◽  
Computational Cost ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Flexibility ◽  
Cross Docking ◽  
Internal Cavities ◽  
The Cross

Motivation Molecular docking is an efficient method to predict the conformations adopted by the ligand within the target binding site. Usually, standard docking protocol involves only one structure to represent the receptor, overlooking the changes in the binding pocket geometry induced by ligand binding. In our previous work, we observed that different conformations of the same target show different volume and shape of the internal cavities (Sessa et al., 2016). Different ligands may stabilize different receptor conformations with different internal cavities. Consequently, the crystallographic data represent the adaptation of a protein to a particular ligand. Cross-docking is a validation procedure consisting in docking a series of ligands into different conformation of the same receptor. Since the structures of the same receptor can be rather different, the cross-docking analyses are typically very poor. In these cases the internal cavity of the buried binding pocket does not have space enough to accommodate all ligands and this can radically affect the outcome and alter the cross-docking results. The changes of the cavity volume might explain the failure of traditional docking method and support the hypothesis that a single representative structure for the receptor is not enough. Keeping target proteins flexible during the docking has a high computational cost. To overcome this limit, our docking strategy is to represent receptor flexibility through an inexpensive method that generates a series of target structures. Starting from a known target structure, we used the molecular dynamics (MD) simulations to explore the conformational changes induced by ligand binding and to collect several snapshots of receptor structures to perform the cross-docking studies. To validate the accuracy of our flexible protocol in docking, we used a set of 10 crystallographic conformations of Androgen Receptor with the same target but with a different ligand. We performed two parallel experiments of docking, one with a rigid protein target and one considering flexible receptor structures. In addition, we compared the results for both experiments in the re-docking and in the cross-docking analysis. Methods Ten receptor structures complexed with a ligand were extracted from the X-ray structures in the PDB database (Berman et al., 2000). Several conformations for each receptor were selected from the molecular dynamics simulations (MD) at regular time intervals (each 500 ps). The MD simulations were performed with the software YASARA Structure 16.2.14 (Krieger & Vriend, 2014) using AMBER14 as force field. The molecular docking simulations were performed using VINA provided in the YASARA package. "Abstract truncated at 3,000 characters - the full version is available in the pdf file"

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