scholarly journals Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 214
Author(s):  
Yoel Rodríguez ◽  
Magdaléna Májeková
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Conformational Changes ◽  
Calcium Ions ◽  
Structural Changes ◽  
Acid Group ◽  
Bilayer Membrane ◽  
Salt Bridges ◽  
Drug Candidates ◽  
Dynamics Simulations

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side chains of several residues, primarily Glu90 and Lys297. All in all, the structural changes induced by the binding of rutin arachidonate to SERCA1a may shift proton balance near the titrable residues Glu771 and Glu309 into neutral species, hence preventing the binding of calcium ions to the transmembrane binding sites and thus affecting calcium homeostasis. Our results could lead towards the design of new types of inhibitors, potential drug candidates for cancer treatment, which could be anchored to the transmembrane region of SERCA1a by a lipophilic fatty acid group.

scholarly journals 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 ◽  
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.

Molecular Dynamics Simulations of HLA-CW4-Β2M-KIR2DL1 Protein and Homology Modeling of a Complex Associated with Psoriasis Disease (HLA-CW6-Β 2M-KIR2DS1)

2021 ◽  
Author(s):  
Mansour H Almatarneh ◽  
Ahmad M Alqaisi ◽  
Enas K Ibrahim ◽  
Ghada G Kayed ◽  
Joshua W Hollett
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Complex Structure ◽  
3D Structure ◽  
Md Simulations ◽  
Salt Bridges ◽  
Small Peptide ◽  
Β2 Microglobulin ◽  
Dynamics Simulations ◽  
The Right

Molecular dynamics (MD) simulation was used to study the interactions of two immune proteins of HLA-Cw4-β2m-KIR2DL1 complex with small peptide QYDDAVYKL (nine amino acids) in an aqueous solution. This study aims to gain a detailed information about the conformational changes and the dynamics of the complex. The right parameters and force field for performing the MD simulations that was needed to calibrate the complex structure were determined. The non-bonded interactions (Electrostatic and van der Waals contributions), H-bond formation, and salt bridges between the ligand HLA-Cw4 and the receptor KIR2DL1 were estimated using the obtained MD trajectories. The buried surface area due to binding was calculated to get insight into the causes of specificity of receptor to ligand and explains mutations experiment. The study concluded that β2-microglobulin, one part of the complex, is not directly interacting with the peptide at the groove; therefore, it could be neglected from simulation. Our results showed that β2-microglobulin does not have any significant effect on the dynamics of the 3D-structure of the complex. This project will help in understanding to optimize candidate drug design, a small peptide that disrupts the interaction, for the optimal biological effect.

scholarly journals Salt bridges gate α-catenin activation at intercellular junctions

2018 ◽  
Vol 29 (2) ◽  
pp. 111-122 ◽  
Author(s):  
Samantha Barrick ◽  
Jing Li ◽  
Xinyu Kong ◽  
Alokananda Ray ◽  
Emad Tajkhorshid ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Mechanical Activation ◽  
Conformational Changes ◽  
Intercellular Junctions ◽  
Salt Bridge ◽  
Salt Bridges ◽  
Equilibrium Binding ◽  
Binding Data ◽  
Dynamics Simulations ◽  
Intercellular Adhesions

Molecular dynamics simulations, equilibrium binding measurements, and fluorescence imaging reveal the influence of a key salt bridge in the mechanical activation of α-catenin at intercellular adhesions. Simulations reveal possible α-catenin conformational changes underlying experimental fluorescence and equilibrium binding data.

scholarly journals The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K

2018 ◽  
Author(s):  
Simon R. Bushell ◽  
Ashley C.W. Pike ◽  
Maria E. Falzone ◽  
Nils J. G. Rorsman ◽  
Chau M Ta ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Conformational Changes ◽  
Chloride Channel ◽  
Autosomal Recessive ◽  
Structural Basis ◽  
Spinocerebellar Ataxia Type ◽  
Channel Activity ◽  
Dynamics Simulations ◽  
In Cells

AbstractMembranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase and ion channel activity, or specific chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident calcium-regulated lipid scramblase. Our crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional structures solved by cryo-EM reveal extensive conformational changes extending from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity. Our results suggest mechanisms by which missense variants of TMEM16K could cause SCAR10 ataxia, providing new hypotheses to explore for therapy.

scholarly journals Small Molecules to Destabilize the ACE2-RBD Complex: A Molecular Dynamics Study for Potential COVID-19 Therapeutics

2020 ◽  
Author(s):  
Meghdad Razizadeh ◽  
Mehdi Nikfar ◽  
Yaling Liu
Keyword(s):  
Molecular Dynamics ◽  
Small Molecules ◽  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Chemical Compounds ◽  
Cell Receptor ◽  
Infection Process ◽  
Host Cell Receptor ◽  
Dynamics Simulations

The ongoing COVID-19 pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, Angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, Molecular docking is employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex are analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

scholarly journals Small Molecules to Destabilize the ACE2-RBD Complex: A Molecular Dynamics Study for Potential COVID-19 Therapeutics

2020 ◽  
Author(s):  
Meghdad Razizadeh ◽  
Mehdi Nikfar ◽  
Yaling Liu
Keyword(s):  
Molecular Dynamics ◽  
Small Molecules ◽  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Chemical Compounds ◽  
Cell Receptor ◽  
Infection Process ◽  
Host Cell Receptor ◽  
Dynamics Simulations

The ongoing COVID-19 pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, Angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, Molecular docking is employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex are analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6709
Author(s):  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Hong Chen ◽  
Ping Xie
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Binding Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Weak Interactions ◽  
Molecular Motor ◽  
Structural Data ◽  
Calculated Binding Energy ◽  
Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

scholarly journals Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renu Wadhwa ◽  
Neetu Singh Yadav ◽  
Shashank P. Katiyar ◽  
Tomoko Yaguchi ◽  
Chohee Lee ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cell Membrane ◽  
Molecular Dynamics Simulations ◽  
Experimental Studies ◽  
Bilayer Membrane ◽  
Withaferin A ◽  
Head Group ◽  
Polar Head Group ◽  
Natural Drugs ◽  
Dynamics Simulations

AbstractPoor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.

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