scholarly journals The Influence of Calcium toward Order/Disorder Conformation of Repeat-in-Toxin (RTX) Structure of Family I.3 Lipase from Pseudomonas fluorescens AMS8

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 579
Author(s):  
Nur Shidaa Mohd Ali ◽  
Abu Bakar Salleh ◽  
Thean Chor Leow ◽  
Raja Noor Zaliha Raja Abd Rahman ◽  
Mohd Shukuri Mohamad Ali
Keyword(s):  
Calcium Binding ◽  
Metal Ion ◽  
Md Simulation ◽  
Structural Changes ◽  
Decisive Role ◽  
Md Simulations ◽  
High Binding Energy ◽  
Docking Analysis ◽  
Repeat Structure ◽  
Functional Dynamics

Calcium-binding plays a decisive role in the folding and stabilization of many RTX proteins, especially for the RTX domain. Although many studies have been conducted to prove the contribution of Ca2+ ion toward the folding and stabilization of RTX proteins, its functional dynamics and conformational structural changes remain elusive. Here, molecular docking and molecular dynamics (MD) simulations were performed to analyze the contribution of Ca2+ ion toward the folding and stabilization of the RTX lipase (AMS8 lipase) structure. AMS8 lipase contains six Ca2+ ions (Ca1–Ca6). Three Ca2+ ions (Ca3, Ca4, and Ca5) were bound to the RTX parallel β-roll motif repeat structure (RTX domain). The metal ion (Ca2+) docking analysis gives a high binding energy, especially for Ca4 and Ca5 which are tightly bound to the RTX domain. The function of each Ca2+ ion is further analyzed using the MD simulation. The removal of Ca3, Ca4, and Ca5 caused the AMS8 lipase structure to become unstable and unfolded. The results suggested that Ca3, Ca4, and Ca5 stabilized the RTX domain. In conclusion, Ca3, Ca4, and Ca5 play a crucial role in the folding and stabilization of the RTX domain, which sustain the integrity of the overall AMS8 lipase structure.

High-resolution MD simulation studies to get mechanistic insights into the urea-induced denaturation of human Sphingosine kinase 1

2021 ◽  
Vol 21 ◽  
Author(s):  
Faez Iqbal Khan ◽  
Shahid Ali ◽  
Wenjing Chen ◽  
Farah Anjum ◽  
Alaa Shafie ◽  
...  
Keyword(s):  
Time Scale ◽  
Md Simulation ◽  
Structural Changes ◽  
Sphingosine Kinase ◽  
Md Simulations ◽  
Sphingosine Kinase 1 ◽  
Cellular Survival ◽  
Constant Form ◽  
The Impact ◽  
Unfolding Kinetics

Background: Sphingosine kinase 1 (SPhK1) is a crucial signaling enzyme involved in cell proliferation, cellular survival, stimulation of angiogenesis, and apoptosis prevention. Recently, we have reported the unfolding kinetics of SPhK1 using molecular dynamics (MD) simulation, circular dichroism and fluorescence spectroscopy. We found that SPhK1 showed a biphasic unfolding with an intermediate state (~ 4.0 M urea). Objective: We aim to understand the impact of MD simulation duration on the structure, function and dynamics of proteins. In order to get deeper insights into the folding mechanism an extended MD simulation is required. Method: Here, we extended the MD simulations time scale from 100 to 300 ns on SPhK1 at increasing urea concentration to explore structural changes in the SPhK1. Results: The results suggested a constant form of the unfolding of SPhK1 upon extending the simulation time scale at different urea concentrations. Furthermore, we showed step by step unfolding and percentage of secondary structure contents in SPhK1 under the influence of urea at each concentration. Conclusion: The results from the current work revealed a uniform pattern of the SPhK1 unfolding at different urea concentrations. This study provides deeper mechanistic insights into the urea-induced denaturation of SPhK1.

Myricetin Preferentially Binds to Interfacial Regions in Domains 1 – 3 to Inhibit Cholesterol-Dependent Cytolysins: A Molecular Docking Study

2020 ◽  
Author(s):  
Rafael Espiritu
Keyword(s):  
Molecular Docking ◽  
Structural Changes ◽  
Docking Study ◽  
Listeriolysin O ◽  
Molecular Docking Study ◽  
Docking Analysis ◽  
Streptolysin O ◽  
Molecule Inhibitor ◽  
Human Cd59 ◽  
Anthrolysin O

<p>Cholesterol-dependent cytolysins (CDCs) are proteinaceous toxins secreted as monomers by some Gram-positive and Gram-negative bacteria that contribute to their pathogenicity. These toxins bind to either cholesterol or human CD59, leading to massive structural changes, toxin oligomerization, formation of very large pores, and ultimately cell death, making these proteins promising targets for inhibition. Myricetin, and its related flavonoids, have been previously identified as a candidate small molecule inhibitor of specific CDCs such as listeriolysin O (LLO) and suilysin (SLY), interfering with their oligomerization. In this work, molecular docking was performed to assess the interaction of myricetin with other CDCs whose crystal structures are already known. Results indicated that although myricetin bound to the hitherto identified cavity in domain 4 (D4), much more efficient and stable binding was obtained in sites along the interfacial regions of domains 1 – 3 (D1 – D3). This was common among the tested CDCs, which was primarily due to much more extensive stabilizing intermolecular interactions, as indicated by post-docking analysis. Specifically, myricetin bound to (1) the interface of the three domains in anthrolysin O (ALO), perfringolysin O (PFO), pneumolysin (PLY), SLY, and vaginolysin (VLY), (2) at/near the D1/D3 interface in LLO and streptolysin O (SLO), and (3) along the D2/D3 interface in intermedilysin (ILY). These findings provide theoretical basis on the possibility of using myricetin and its related compounds as a broad-spectrum inhibitor of CDCs to potentially address the diseases associated with these pathogens.</p>

A comprehensive in silico study towards understanding the inhibitory mechanism of Lactoperoxidase by Dapsone and Propofol

2020 ◽  
Vol 16 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Gizachew Muluneh Amera ◽  
Jayaraman Muthukumaran ◽  
Rashmi Prabha Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Protoporphyrin Ix ◽  
Md Simulations ◽  
Prosthetic Group ◽  
Drug Molecules ◽  
Group A ◽  
Complex Forms ◽  
Covalently Linked

Introduction: Lactoperoxidase (LPO) is a member of mammalian heme peroxidase family and is an enzyme of innate immune system. It possesses a covalently linked heme prosthetic group (a derivative of protoporphyrin IX) in its active site. LPO catalyzes the oxidation of halides and pseudohalides in the presence of hydrogen peroxide (H2O2) and shows a broad range of antimicrobial activity. Methods: In this study, we have used two pharmaceutically important drug molecules, namely dapsone and propofol, which are earlier reported as potent inhibitors of LPO. Whereas the stereochemistry and mode of binding of dapsone and propofol to LPO is still not known because of the lack of the crystal structure of LPO with these two drugs. In order to fill this gap, we utilized molecular docking and molecular dynamics (MD) simulation studies of LPO in native and complex forms with dapsone and propofol. Results: From the docking results, the estimated binding free energy (ΔG) of -9.25 kcal/mol (Ki = 0.16 μM) and -7.05 kcal/mol (Ki = 6.79 μM) was observed for dapsone, and propofol, respectively. The standard error of Auto Dock program is 2.5 kcal/mol; therefore, molecular docking results alone were inconclusive. Conclusion: To further validate the docking results, we performed MD simulation on unbound, and two drugs bounded LPO structures. Interestingly, MD simulations results explained that the structural stability of LPO-Propofol complex was higher than LPO-Dapsone complex. The results obtained from this study establish the mode of binding and interaction pattern of the dapsone and propofol to LPO as inhibitors.

scholarly journals Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Baolei Yuan ◽  
Jordy Homing Lam ◽  
Jun Zhou ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Md Simulation ◽  
Potential Role ◽  
Md Simulations ◽  
Full Length ◽  
Inflammasome Activation ◽  
Simulation Studies ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

scholarly journals Correlation of membrane protein conformational and functional dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raghavendar Reddy Sanganna Gari ◽  
Joel José Montalvo‐Acosta ◽  
George R. Heath ◽  
Yining Jiang ◽  
Xiaolong Gao ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Conformational Changes ◽  
Single Channel ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
High Temporal Resolution ◽  
Dependent Manner ◽  
Functional Dynamics ◽  
Ph Dependent ◽  
Open States

AbstractConformational changes in ion channels lead to gating of an ion-conductive pore. Ion flux has been measured with high temporal resolution by single-channel electrophysiology for decades. However, correlation between functional and conformational dynamics remained difficult, lacking experimental techniques to monitor sub-millisecond conformational changes. Here, we use the outer membrane protein G (OmpG) as a model system where loop-6 opens and closes the β-barrel pore like a lid in a pH-dependent manner. Functionally, single-channel electrophysiology shows that while closed states are favored at acidic pH and open states are favored at physiological pH, both states coexist and rapidly interchange in all conditions. Using HS-AFM height spectroscopy (HS-AFM-HS), we monitor sub-millisecond loop-6 conformational dynamics, and compare them to the functional dynamics from single-channel recordings, while MD simulations provide atomistic details and energy landscapes of the pH-dependent loop-6 fluctuations. HS-AFM-HS offers new opportunities to analyze conformational dynamics at timescales of domain and loop fluctuations.

scholarly journals Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations

2021 ◽  
pp. 1-12
Author(s):  
Haiyan Li ◽  
Zanxia Cao ◽  
Guodong Hu ◽  
Liling Zhao ◽  
Chunling Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Changes ◽  
Binding Protein ◽  
Network Models ◽  
Md Simulations ◽  
Protein Domain ◽  
Opening Angle ◽  
Conformation Changes ◽  
Wide Range ◽  
Ribose Binding Protein

BACKGROUND: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations. OBJECTIVE: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models. METHODS: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations. RESULTS: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation. CONCLUSIONS: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.

scholarly journals Fully Atomistic Molecular Dynamics Computation of Physico-Mechanical Properties of PB, PS, and SBS

Nanomaterials ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 1088 ◽  
Author(s):  
Yang Kang ◽  
Dunhong Zhou ◽  
Qiang Wu ◽  
Fuyan Duan ◽  
Rufang Yao ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Strain Rate ◽  
Strain Hardening ◽  
Md Simulation ◽  
Md Simulations ◽  
Strain Rates ◽  
Young’S Moduli ◽  
Plastic Modulus ◽  
Styrene Butadiene ◽  
Butadiene Styrene

The physical properties—including density, glass transition temperature (Tg), and tensile properties—of polybutadiene (PB), polystyrene (PS) and poly (styrene-butadiene-styrene: SBS) block copolymer were predicted by using atomistic molecular dynamics (MD) simulation. At 100 K, for PB and SBS under uniaxial tension with strain rate ε ˙ = 1010 s−1 and 109 s−1, their stress–strain curves had four features, i.e., elastic, yield, softening, and strain hardening. At 300 K, the tensile curves of the three polymers with strain rates between 108 s−1 and 1010 s−1 exhibited strain hardening following elastic regime. The values of Young’s moduli of the copolymers were independent of strain rate. The plastic modulus of PS was independent of strain rate, but the Young’s moduli of PB and SBS depended on strain rate under the same conditions. After extrapolating the Young’s moduli of PB and SBS at strain rates of 0.01–1 s−1 by the linearized Eyring-like model, the predicted results by MD simulations were in accordance well with experimental results, which demonstrate that MD results are feasible for design of new materials.

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