scholarly journals Lipid-Uptake Pathways and Lipid-Protein interactions in P-glycoprotein Revealed by Coarse-Grained Molecular Dynamics Simulations

2017 ◽  
Author(s):  
E. Barreto-Ojeda ◽  
V. Corradi ◽  
R.-X. Gu ◽  
D.P. Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Experimental Studies ◽  
Md Simulations ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Substrate Uptake ◽  
Lipid Uptake ◽  
P Glycoprotein ◽  
Dynamics Simulations

AbstractP-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids and lipid-like molecules. Due to its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance (MDR). Although P-gp is one of the most studied members of ABC-transporters, the mechanism of how its substrates access the cavity remains unclear. In this work, we performed coarse-grained (CG) molecular dynamics (MD) simulations to explore possible pathways of lipid-uptake in the inward-facing conformation of P-gp embedded in bilayers with different PC:PE lipid ratios. Our results show that in the inward facing orientation only lipids from the lower leaflet are taken up by the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid binding sites, in good agreement with previous experimental studies. Our results show no selectivity for PC vs. PE lipids. We offer several examples of lipid uptake-pathways for PC and PE lipids that help to elucidate the molecular mechanism of substrate-uptake in P-gp.

scholarly journals Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein

2018 ◽  
Vol 150 (3) ◽  
pp. 417-429 ◽  
Author(s):  
Estefania Barreto-Ojeda ◽  
Valentina Corradi ◽  
Ruo-Xu Gu ◽  
D. Peter Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Experimental Studies ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dynamics Simulations ◽  
Positively Charged ◽  
Coarse Grained Molecular Dynamics

P-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids, and lipid-like molecules. Because of its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance. Although P-gp is one of the most studied ABC transporters, the mechanism by which its substrates access the cavity remains unclear. In this study, we perform coarse-grained molecular dynamics simulations to explore possible lipid access pathways in the inward-facing conformation of P-gp embedded in bilayers of different lipid compositions. In the inward-facing orientation, only lipids from the lower leaflet access the cavity of the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid-binding sites at the portals and within the cavity, which is in good agreement with previous experimental studies. This work includes several examples of lipid pathways for phosphatidylcholine and phosphatidylethanolamine lipids that help elucidate the molecular mechanism of lipid binding in P-gp.

scholarly journals Ganglioside-Lipid and Ganglioside-Protein Interactions Revealed by Coarse-Grained and Atomistic Molecular Dynamics Simulations

2016 ◽  
Vol 121 (15) ◽  
pp. 3262-3275 ◽  
Author(s):  
Ruo-Xu Gu ◽  
Helgi I. Ingólfsson ◽  
Alex H. de Vries ◽  
Siewert J. Marrink ◽  
D. Peter Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Protein Interactions ◽  
Coarse Grained ◽  
Dynamics Simulations

Interactions of peripheral proteins with model membranes as viewed by molecular dynamics simulations

2014 ◽  
Vol 42 (5) ◽  
pp. 1418-1424 ◽  
Author(s):  
Antreas C. Kalli ◽  
Mark S. P. Sansom
Keyword(s):  
Lipid Bilayers ◽  
Molecular Mechanisms ◽  
Phospholipid Composition ◽  
Md Simulations ◽  
Multiscale Simulation ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Peripheral Proteins ◽  
Dynamics Simulations ◽  
Phosphatidylinositol Phosphates

Many cellular signalling and related events are triggered by the association of peripheral proteins with anionic lipids in the cell membrane (e.g. phosphatidylinositol phosphates or PIPs). This association frequently occurs via lipid-binding modules, e.g. pleckstrin homology (PH), C2 and four-point-one, ezrin, radixin, moesin (FERM) domains, present in peripheral and cytosolic proteins. Multiscale simulation approaches that combine coarse-grained and atomistic MD simulations may now be applied with confidence to investigate the molecular mechanisms of the association of peripheral proteins with model bilayers. Comparisons with experimental data indicate that such simulations can predict specific peripheral protein–lipid interactions. We discuss the application of multiscale MD simulation and related approaches to investigate the association of peripheral proteins which contain PH, C2 or FERM-binding modules with lipid bilayers of differing phospholipid composition, including bilayers containing multiple PIP molecules.

Effective interaction between small unilamellar vesicles as probed by coarse-grained molecular dynamics simulations

2014 ◽  
Vol 86 (2) ◽  
pp. 215-222 ◽  
Author(s):  
Wataru Shinoda ◽  
Michael L. Klein
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Effective Interaction ◽  
Md Simulations ◽  
Coarse Grained ◽  
Repulsive Interaction ◽  
Spontaneous Curvature ◽  
Unilamellar Vesicles ◽  
Small Unilamellar Vesicles ◽  
Dynamics Simulations

Abstract A series of molecular dynamics (MD) simulations has been undertaken to investigate the effective interaction between vesicles including PC (phosphatidylcholine) and PE (phosphatidylethanolamine) lipids using the Shinoda–DeVane–Klein coarse-grained force field. No signatures of fusion were detected during MD simulations employing two apposed unilamellar vesicles, each composed of 1512 lipid molecules. Association free energy of the two stable vesicles depends on the lipid composition. The two PC vesicles exhibit a purely repulsive interaction with each other, whereas two PE vesicles show a free energy gain at the contact. A mixed PC/PE (1:1) vesicle shows a higher flexibility having a lower energy barrier on the deformation, which is caused by lipid sorting within each leaflet of the membranes. With a preformed channel or stalk between proximal membranes, PE molecules contribute to stabilize the stalk. The results suggest that the lipid components forming the membrane with a negative spontaneous curvature contribute to stabilize the stalk between two vesicles in contact.

scholarly journals Coupling all-atom molecular dynamics simulations of ions in water with Brownian dynamics

2016 ◽  
Vol 472 (2186) ◽  
pp. 20150556 ◽  
Author(s):  
Radek Erban
Keyword(s):  
Molecular Dynamics ◽  
Differential Equations ◽  
Aqueous Solutions ◽  
Molecular Dynamics Simulations ◽  
Brownian Dynamics ◽  
Md Simulations ◽  
Coarse Grained ◽  
Computational Domain ◽  
Coarse Grained Model ◽  
Dynamics Simulations

Molecular dynamics (MD) simulations of ions (K + , Na + , Ca 2+ and Cl − ) in aqueous solutions are investigated. Water is described using the SPC/E model. A stochastic coarse-grained description for ion behaviour is presented and parametrized using MD simulations. It is given as a system of coupled stochastic and ordinary differential equations, describing the ion position, velocity and acceleration. The stochastic coarse-grained model provides an intermediate description between all-atom MD simulations and Brownian dynamics (BD) models. It is used to develop a multiscale method which uses all-atom MD simulations in parts of the computational domain and (less detailed) BD simulations in the remainder of the domain.

scholarly journals Coarse-grained molecular dynamics simulations of nanoplastics interacting with a hydrophobic environment in aqueous solution

RSC Advances ◽  
2021 ◽  
Vol 11 (44) ◽  
pp. 27734-27744
Author(s):  
Lorenz F. Dettmann ◽  
Oliver Kühn ◽  
Ashour A. Ahmed
Keyword(s):  
Carbon Nanotubes ◽  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Water Treatment ◽  
Md Simulations ◽  
Coarse Grained ◽  
Treatment Technologies ◽  
Dynamics Simulations ◽  
Binding Mechanisms ◽  
Soil And Water

The binding mechanisms of nanoplastics (NPs) to carbon nanotubes as hydrophobic environmental systems have been explored by coarse-grained MD simulations. The results could be closely connected to fate of NPs in soil and water treatment technologies.

scholarly journals Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5696
Author(s):  
Wei Lim Chong ◽  
Koollawat Chupradit ◽  
Sek Peng Chin ◽  
Mai Mai Khoo ◽  
Sook Mei Khor ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Protein Binding ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Single Point ◽  
Md Simulations ◽  
Nanoparticle Tracking Analysis ◽  
Buffer Solution ◽  
Dynamics Simulations

Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

scholarly journals Extending the Martini coarse-grained forcefield to N-glycans

2020 ◽  
Author(s):  
Aishwary T. Shivgan ◽  
Jan K. Marzinek ◽  
Roland G. Huber ◽  
Alexander Krah ◽  
Richard H. Henchman ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Experimental Studies ◽  
Md Simulations ◽  
Vital Role ◽  
Distribution Functions ◽  
Coarse Grained ◽  
Carbohydrate Binding ◽  
Free Energies ◽  
Cellular Processes ◽  
Complex Glycans

AbstractGlycans play a vital role in a large number of cellular processes. Their complex and flexible nature hampers structure-function studies using experimental techniques. Molecular dynamics (MD) simulations can help in understanding dynamic aspects of glycans if the forcefield (FF) parameters used can reproduce key experimentally observed properties. Here, we present optimized coarse-grained (CG) Martini FF parameters for N-glycans, calibrated against experimentally derived binding affinities for lectins. The CG bonded parameters were obtained from atomistic (ATM) simulations for different glycan topologies including high mannose and complex glycans with various branching patterns. In the CG model, additional elastic networks are shown to improve maintenance of the overall conformational distribution. Solvation free energies and octanol-water partition coefficients were also calculated for various n-glycan disaccharide combinations. When using standard Martini non-bonded parameters, we observed that glycans spontaneously aggregated in the solution and required down-scaling of their interactions for reproduction of ATM model radial distribution functions. We also optimised the non-bonded interactions for glycans interacting with seven lectin candidates and show that scaling down the glycan-protein interactions can reproduce free energies obtained from experimental studies. These parameters should be of use in studying the role of glycans in various glycoproteins, carbohydrate binding proteins (CBPs) as well as their complexes, while benefiting from the efficiency of CG sampling.

scholarly journals Multiscale Modeling of Structure, Transport and Reactivity in Alkaline Fuel Cell Membranes: Combined Coarse-Grained, Atomistic and Reactive Molecular Dynamics Simulations

Polymers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1289 ◽  
Author(s):  
Dengpan Dong ◽  
Weiwei Zhang ◽  
Adam Barnett ◽  
Jibao Lu ◽  
Adri van Duin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Coarse Grained ◽  
Anion Exchange Membranes ◽  
Reactive Molecular Dynamics ◽  
Advantages And Disadvantages ◽  
Ionic Groups ◽  
Dynamics Simulations ◽  
Equilibrium Morphology ◽  
Hydrated Anion

In this study, molecular dynamics (MD) simulations of hydrated anion-exchange membranes (AEMs), comprised of poly(p-phenylene oxide) (PPO) polymers functionalized with quaternary ammonium cationic groups, were conducted using multiscale coupling between three different models: a high-resolution coarse-grained (CG) model; Atomistic Polarizable Potential for Liquids, Electrolytes and Polymers (APPLE&P); and ReaxFF. The advantages and disadvantages of each model are summarized and compared. The proposed multiscale coupling utilizes the strength of each model and allows sampling of a broad spectrum of properties, which is not possible to sample using any of the single modeling techniques. Within the proposed combined approach, the equilibrium morphology of hydrated AEM was prepared using the CG model. Then, the morphology was mapped to the APPLE&P model from equilibrated CG configuration of the AEM. Simulations using atomistic non-reactive force field allowed sampling of local hydration structure of ionic groups, vehicular transport mechanism of anion and water, and structure equilibration of water channels in the membrane. Subsequently, atomistic AEM configuration was mapped to ReaxFF reactive model to investigate the Grotthuss mechanism in the hydroxide transport, as well as the AEM chemical stability and degradation mechanisms. The proposed multiscale and multiphysics modeling approach provides valuable input for the materials-by-design of novel polymeric structures for AEMs.

Revisiting stress–strain behavior and mechanical reinforcement of polymer nanocomposites from molecular dynamics simulations

2020 ◽  
Vol 22 (29) ◽  
pp. 16760-16771 ◽  
Author(s):  
Jianxiang Shen ◽  
Xiangsong Lin ◽  
Jun Liu ◽  
Xue Li
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Polymer Nanocomposites ◽  
Md Simulations ◽  
Coarse Grained ◽  
Stress Strain ◽  
Mechanical Reinforcement ◽  
Strain Behavior ◽  
Nanoparticle Interactions ◽  
Dynamics Simulations

Through coarse-grained MD simulations, the effects of nanoparticle properties, polymer–nanoparticle interactions, chain crosslinks and temperature on the stress–strain behavior and mechanical reinforcement of PNCs are comprehensively investigated.

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