Effect of pH on the Supramolecular Structure of Helicobacter pylori Urease by Molecular Dynamics Simulations

The effect of pH on the supramolecular structure of Helicobacter pylori urease was studied by means of molecular dynamics simulations at seven different pHs. Appropriate urease charge distributions were calculated using a semi-grand canonical Monte Carlo (SGCMC) procedure that assigns each residue’s charge state depending on the assigned individual pKa obtained by PROPKA. The effect of pH on protein stability has been analyzed through root-mean-square deviation (RMSD), radius of gyration (RG), solvent-accessible surface area (SASA), hydrogen bonds (HB) and salt bridges (SB). Urease catalyses the hydrolysis of urea in 12 active sites that are covered by mobile regions that act like flaps. The mobility of these flaps is increased at acidic pHs. However, extreme acidic conditions cause urease to have the least number of stabilizing interactions. This initiates the process of denaturalization, wherein the four (αβ)3 subunits of the global structure ((αβ)3)4 of urease start to separate.

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Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations

International Journal of Molecular Sciences ◽

10.3390/ijms22147375 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7375

Author(s):

Julie Ledoux ◽

Alain Trouvé ◽

Luba Tchertanov

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Tertiary Structure ◽

Average Distance ◽

Intrinsic Disorder ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Hydrophobic Core ◽

Direct Evaluation ◽

Dynamics Simulations

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.

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Dispersion state phase diagram of citrate-coated metallic nanoparticles in saline solutions

Nature Communications ◽

10.1038/s41467-020-19164-3 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Sebastian Franco-Ulloa ◽

Giuseppina Tatulli ◽

Sigbjørn Løland Bore ◽

Mauro Moglianetti ◽

Pier Paolo Pompa ◽

...

Keyword(s):

Molecular Dynamics ◽

Ionic Strength ◽

Molecular Dynamics Simulations ◽

Metal Nanoparticles ◽

Metallic Nanoparticles ◽

Free Energy Calculations ◽

Coarse Grained ◽

Solvent Accessible Surface Area ◽

Dispersion State ◽

Dynamics Simulations

Abstract The fundamental interactions underlying citrate-mediated chemical stability of metal nanoparticles, and their surface characteristics dictating particle dispersion/aggregation in aqueous solutions, are largely unclear. Here, we developed a theoretical model to estimate the stoichiometry of small, charged ligands (like citrate) chemisorbed onto spherical metallic nanoparticles and coupled it with atomistic molecular dynamics simulations to define the uncovered solvent-accessible surface area of the nanoparticle. Then, we integrated coarse-grained molecular dynamics simulations and two-body free energy calculations to define dispersion state phase diagrams for charged metal nanoparticles in a range of medium’s ionic strength, a known trigger for aggregation. Ultraviolet-visible spectroscopy experiments of citrate-capped nanocolloids validated our predictions and extended our results to nanoparticles up to 35 nm. Altogether, our results disclose a complex interplay between the particle size, its surface charge density, and the ionic strength of the medium, which ultimately clarifies how these variables impact colloidal stability.

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Molecular Dynamics Simulations on the Demolding Process for Nanostructures in Injection Molding

Micromachines ◽

10.3390/mi10100636 ◽

2019 ◽

Vol 10 (10) ◽

pp. 636 ◽

Cited By ~ 1

Author(s):

Can Weng ◽

Dongjiao Yang ◽

Mingyong Zhou

Keyword(s):

Molecular Dynamics ◽

Injection Molding ◽

Molecular Dynamics Simulations ◽

Interaction Mechanism ◽

Mold Insert ◽

Sharp Decrease ◽

Average Density ◽

Radius Of Gyration ◽

Good Shape ◽

Dynamics Simulations

Injection molding is one of the most potential techniques for fabricating polymeric products in large numbers. The filling process, but also the demolding process, influence the quality of injection-molded nanostructures. In this study, nano-cavities with different depth-to-width ratios (D/W) were built and molecular dynamics simulations on the demolding process were conducted. Conformation change and density distribution were analyzed. Interfacial adhesion was utilized to investigate the interaction mechanism between polypropylene (PP) and nickel mold insert. The results show that the separation would first happen at the shoulder of the nanostructures. Nanostructures and the whole PP layer are both stretched, resulting in a sharp decrease in average density after demolding. The largest increase in the radius of gyration and lowest velocity can be observed in 3:1 nanostructure during the separation. Deformation on nanostructure occurs, but nevertheless the whole structure is still in good shape. The adhesion energy gets higher with the increase of D/W. The demolding force increases quickly to the peak point and then gradually decreases to zero. The majority of the force comes from the adhesion and friction on the nanostructure due to the interfacial interaction.

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Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

Processes ◽

10.3390/pr7110850 ◽

2019 ◽

Vol 7 (11) ◽

pp. 850

Author(s):

Yu Zou ◽

Zhiwei Liu ◽

Zhiqiang Zhu ◽

Zhenyu Qian

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Therapeutic Strategy ◽

Binding Capacity ◽

Salt Bridges ◽

Drug Candidates ◽

Binding Behavior ◽

Dynamics Simulations ◽

Structural Influence ◽

Β Sheet

The pathogenesis of Parkinson’s disease (PD) is closely associated with the aggregation of α-synuclein (αS) protein. Finding the effective inhibitors of αS aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine (NE), can effectively inhibit αS aggregation and disrupt the preformed αS fibrils. However, the atomistic details of αS-DA/NE interaction remain unclear. Here, using molecular dynamics simulations, we investigated the binding behavior of DA/NE molecules and their structural influence on αS44–96 (Greek-key-like core of full length αS) protofibrillar tetramer. Our results showed that DA/NE molecules destabilize αS protofibrillar tetramer by disrupting the β-sheet structure and destroying the intra- and inter-peptide E46–K80 salt bridges, and they can also destroy the inter-chain backbone hydrogen bonds. Three binding sites were identified for both DA and NE molecules interacting with αS tetramer: T54–T72, Q79–A85, and F94–K96, and NE molecules had a stronger binding capacity to these sites than DA. The binding of DA/NE molecules to αS tetramer is dominantly driven by electrostatic and hydrogen bonding interactions. Through aromatic π-stacking, DA and NE molecules can bind to αS protofibril interactively. Our work reveals the detailed disruptive mechanism of protofibrillar αS oligomer by DA/NE molecules, which is helpful for the development of drug candidates against PD. Given that exercise as a stressor can stimulate DA/NE secretion and elevated levels of DA/NE could delay the progress of PD, this work also enhances our understanding of the biological mechanism by which exercise prevents and alleviates PD.

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Insight into the key active sites of afChiA1 based on molecular dynamics simulations and free energy calculations

Molecular Simulation ◽

10.1080/08927022.2016.1148265 ◽

2016 ◽

Vol 42 (12) ◽

pp. 1024-1028

Author(s):

Xiao D. Niu ◽

Zhuo Lv ◽

Xin R. Zhou ◽

Hong S. Wang

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Dynamics Simulations ◽

Active Sites ◽

Free Energy Calculations ◽

Energy Calculations ◽

Dynamics Simulations ◽

Insight Into

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How well do force fields capture the strength of salt bridges in proteins?

10.1101/272799 ◽

2018 ◽

Author(s):

Mustapha Carab Ahmed ◽

Elena Papaleo ◽

Kresten Lindorff-Larsen

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Force Fields ◽

Salt Bridge ◽

Salt Bridges ◽

Enhanced Sampling ◽

Important Interaction ◽

Close Proximity ◽

The Stability ◽

Dynamics Simulations

AbstractSalt bridges form between pairs of ionisable residues in close proximity and are important interactions in proteins. While salt bridges are known to be important both for protein stability, recognition and regulation, we still do not have fully accurate predictive models to assess the energetic contributions of salt bridges. Molecular dynamics simulations is one technique that may be used study the complex relationship between structure, solvation and energetics of salt bridges, but the accuracy of such simulations depend on the force field used. We have used NMR data on the B1 domain of protein G (GB1) to benchmark molecular dynamics simulations. Using enhanced sampling simulations, we calculated the free energy of forming a salt bridge for three possible ionic interactions in GB1. The NMR experiments showed that these interactions are either not formed, or only very weakly formed, in solution. In contrast, we show that the stability of the salt bridges is slightly overestimated in simulations of GB1 using six commonly used combinations of force fields and water models. We therefore conclude that further work is needed to refine our ability to model quantitatively the stability of salt bridges through simulations, and that comparisons between experiments and simulations will play a crucial role in furthering our understanding of this important interaction.

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Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

10.20944/preprints201901.0097.v1 ◽

2019 ◽

Author(s):

Khanittha Kerdpol ◽

Jintawee Kicuntod ◽

Peter Wolschann ◽

Seiji Mori ◽

Chompoonut Rungnim ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Conformational Changes ◽

Inclusion Complexation ◽

Water Soluble ◽

Replica Exchange ◽

Radius Of Gyration ◽

Replica Exchange Molecular Dynamics ◽

Beta Cyclodextrin ◽

Dynamics Simulations

2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. Understanding of the structural properties of HPβCD and its derivatives based on the number of 2-hydroxypropyl (HP) substituents at the a-D-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution called as 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have lower chance to flip than in βCD. Also, HP groups are occasionally blocking the hydrophobic cavity of HPβCDs, thus hindering the drug inclusion. We found that HPβCDs with high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitution are even more probable to be blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation based on our conformational analyses such as structural distortion, radius of gyration, circularity and cavity self-closure of the HPβCDs.

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How Reactive are Druggable Cysteines in Protein Kinases?

10.26434/chemrxiv.5483368 ◽

2017 ◽

Author(s):

Ernest Awoonor-Williams ◽

Christopher Rowley

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Protein Kinases ◽

Active Sites ◽

Cysteine Residues ◽

Dynamics Simulations

This manuscript presents our molecular dynamics simulations of kinase proteins. The pKa's of cysteine residues in the active sites were computed using molecular dynamics simulations in order to access their reactivity towards covalent-modifier drugs.

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