scholarly journals Binding Orientations and Lipid Interactions of Human Amylin at Zwitterionic and Anionic Lipid Bilayers

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Zhenyu Qian ◽  
Yan Jia ◽  
Guanghong Wei
Keyword(s):  
Lipid Bilayers ◽  
Helical Structure ◽  
Terminal Region ◽  
Islet Amyloid ◽  
Anionic Lipid ◽  
Multiple Binding ◽  
Preferential Binding ◽  
Dynamics Simulations ◽  
Binding Orientations ◽  
Human Amylin

Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic isletβ-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C-terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N-terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

scholarly journals Adsorption of Chiral [5]-Aza[5]helicenes on DNA Can Modify Its Hydrophilicity and Affect Its Chiral Architecture: A Molecular Dynamics Study

Materials ◽  
2020 ◽  
Vol 13 (21) ◽  
pp. 5031
Author(s):  
Giuseppina Raffaini ◽  
Andrea Mele ◽  
Tullio Caronna
Keyword(s):  
Molecular Dynamics ◽  
Competitive Adsorption ◽  
Double Helix ◽  
Helical Structure ◽  
High Concentration ◽  
Racemic Mixtures ◽  
Preferential Binding ◽  
Biological Environment ◽  
Dynamics Simulations ◽  
Self Aggregation

Helicenes are interesting chiral molecules without asymmetric carbon atoms but with intrinsic chirality. Functionalized 5-Aza[5]helicenes can form non-covalent complexes with anticancer drugs and therefore be potential carriers. The paper highlights the different structural selectivity for DNA binding for two enantiopure compounds and the influence of concentration on their adsorption and self-aggregation process. In this theoretical study based on atomistic molecular dynamics simulations the interaction between (M)- and (P)-5-Aza[5]helicenes with double helix B-DNA is investigated. At first the interaction of single pure enantiomer with DNA is studied, in order to find the preferred site of interaction at the major or minor groove. Afterwards, the interaction of the enantiomers at different concentrations was investigated considering both competitive adsorption on DNA and possible helicenes self-aggregation. Therefore, racemic mixtures were studied. The helicenes studied are able to bind DNA modulating or locally modifying its hydrophilic surface into hydrophobic after adsorption of the first helicene layer partially covering the negative charge of DNA at high concentration. The (P)-enantiomer shows a preferential binding affinity of DNA helical structure even during competitive adsorption in the racemic mixtures. These DNA/helicenes non-covalent complexes exhibit a more hydrophobic exposed surface and after self-aggregation a partially hidden DNA chiral architecture to the biological environment.

scholarly journals Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

2021 ◽  
Vol 22 (18) ◽  
pp. 10047
Author(s):  
Carina Höring ◽  
Marcus Conrad ◽  
Christian A. Söldner ◽  
Jinan Wang ◽  
Heinrich Sticht ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Histamine Receptors ◽  
Accelerated Molecular Dynamics ◽  
Preferential Binding ◽  
Binding Cavity ◽  
Pharmacological Potential ◽  
Dynamics Simulations ◽  
Binding Orientations ◽  
Protein Recruitment

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

scholarly journals Do Cyclotides bind Lipid Bilayers: Molecular Dynamics Simulations of Kalata B1 and POPC/POPE membranes

2014 ◽  
Author(s):  
Neville Y. Forlemu ◽  
Patrick Coppock
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Electrostatic Interactions ◽  
Close Contact ◽  
Amino Acid Residues ◽  
Kalata B1 ◽  
Preferential Binding ◽  
Mechanism Of Interaction ◽  
Dynamics Simulations ◽  
Lipid Layers

Cyclotides are cyclic antimicrobial peptides (APs) that offer promising features for the development of efficient pharmaceutical therapies. Their efficacy is still hampered by lack of molecular details of their mechanism/mode of action. We have used unconstrained an all-atom molecular dynamics (MD) simulation to investigate the interactions between a representative cyclotide (kalata B1) and bilayers comprising 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) lipids. Kalata B1 is attracted to the surface of both lipid layers through close contact interactions. There is preferential binding on POPE,POPG layer as opposed to POPC mainly due to stronger electrostatic interactions. Kalata B1 in the last 60 ns of the simulation remains in close contact with the lipid headgroups of POPE using 5 amino acid residues (VAL, ASN, THR, GLU, TRP). This initial data suggest that these surface interactions promote peptide distribution similar to the carpet model mechanism of interaction.

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