scholarly journals Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8

2021 ◽  
Author(s):  
Xiaoyu Wang ◽  
Yu Chen ◽  
Steven Zhang ◽  
Jinxia Nancy Deng
Keyword(s):  
Small Molecule ◽  
Van Der Waals ◽  
Biological Response ◽  
Binding Pocket ◽  
Van Der Waals Interactions ◽  
Side Chain ◽  
Dynamic Simulations ◽  
Hydrophobic Nature ◽  
Dynamics Simulations ◽  
Small Molecule Modulators

TLR7 and TLR8 are key members of the Toll-like receptor family, playing crucial roles in the signaling pathways of innate immunity, and thus become attractive therapeutic targets of many diseases including infections and cancer. Although TLR7 and TLR8 show a highly degree of sequence homology, their biological response to small molecule binding is very different. Aiming to understand the mechanism of selective profiles of small molecule modulators against TLR7 and TLR8, we carried out molecular dynamic simulations on three imidazoquinoline derivatives bound to the receptors separately. They are Resiquimod (R), Hybrid-2 (H), and Gardiquimod (G), selective agonists of TLR7 and TLR8. Our MD trajectories indicated that in the complex of TLR7-R and TLR7-G, the two chains forming the TLR7 dimer tended to remain “open” conformation, while the rest systems maintained in the closed format. The agonists R, H, and G developed conformational deviation mainly on the aliphatic tail. Furthermore, we attempted to quantify the selectivity between TLR7 and TLR8 by binding free energies via MM-GBSA method. It showed that the three selected modulators were more favorable for TLR7 than TLR8, and the ranking from the strongest to the weakest was H, R and G, aligning well with experiment data. In the TLR7, the flexible and hydrophobic aliphatic side chain of H has stronger van der Waals interactions with Val381 and Phe351 but only pick up interaction with one amino acid residue i.e. Tyr353 of TLR8. Unsurprisingly, the positively charged side chain of G has less favor interaction with Ile585 of TLR7 and Val573 of TLR8 explaining G is weak agonist in both TLR7 and TLR8. All three imidazoquinolines can form stable hydrogen bonds with Asp555 of TLR7 and the corresponding Asp543 of TLR8. In brief, the set of total 400ns MD studies sheds light on the potential selective mechanisms of agonists towards TLR7 and TLR8, indicating the van der Waals interaction as the driving force for the agonists binding, thus provides us insights for more potent and selective modulators to cooperate with the hydrophobic nature of the binding pocket.

scholarly journals The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain.

2000 ◽  
Vol 47 (1) ◽  
pp. 65-78 ◽  
Author(s):  
J Mazerski ◽  
K Muchewicz
Keyword(s):  
Conformational Changes ◽  
Ring System ◽  
Van Der Waals Interactions ◽  
Side Chain ◽  
Intercalation Complex ◽  
Highly Active ◽  
Antitumor Compounds ◽  
Chemical Constitution ◽  
Modelling Techniques ◽  
Dynamics Simulations

Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i) in water, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.

Structures of the PKC-ι kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533–551 in the C-terminal tail and their roles in ATP binding

2010 ◽  
Vol 66 (5) ◽  
pp. 577-583 ◽  
Author(s):  
Tetsuo Takimura ◽  
Kenji Kamata ◽  
Kazuhiro Fukasawa ◽  
Hirokazu Ohsawa ◽  
Hideya Komatani ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Van Der Waals Interactions ◽  
Side Chain ◽  
Phosphoryl Transfer ◽  
Atp Binding ◽  
Cellular Functions ◽  
Substrate Complex ◽  
Wide Range

Protein kinase C (PKC) plays an essential role in a wide range of cellular functions. Although crystal structures of the PKC-θ, PKC-ι and PKC-βII kinase domains have previously been determined in complexes with small-molecule inhibitors, no structure of a PKC–substrate complex has been determined. In the previously determined PKC-ι complex, residues 533–551 in the C-terminal tail were disordered. In the present study, crystal structures of the PKC-ι kinase domain in its ATP-bound and apo forms were determined at 2.1 and 2.0 Å resolution, respectively. In the ATP complex, the electron density of all of the C-terminal tail residues was well defined. In the structure, the side chain of Phe543 protrudes into the ATP-binding pocket to make van der Waals interactions with the adenine moiety of ATP; this is also observed in other AGC kinase structures such as binary and ternary substrate complexes of PKA and AKT. In addition to this interaction, the newly defined residues around the turn motif make multiple hydrogen bonds to glycine-rich-loop residues. These interactions reduce the flexibility of the glycine-rich loop, which is organized for ATP binding, and the resulting structure promotes an ATP conformation that is suitable for the subsequent phosphoryl transfer. In the case of the apo form, the structure and interaction mode of the C-terminal tail of PKC-ι are essentially identical to those of the ATP complex. These results indicate that the protein structure is pre-organized before substrate binding to PKC-ι, which is different from the case of the prototypical AGC-branch kinase PKA.

scholarly journals A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Wesley M. Botello-Smith ◽  
Wenjuan Jiang ◽  
Han Zhang ◽  
Alper D. Ozkan ◽  
Yi-Chun Lin ◽  
...  
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Calcium Imaging ◽  
Rational Design ◽  
Binding Pocket ◽  
Mechanical Forces ◽  
Biological Processes ◽  
Clinical Value ◽  
Mechanical Threshold ◽  
Dynamics Simulations

Abstract Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel’s mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value.

Effect of van der Waals Interaction Strength and Nanocluster Size on the Dynamical and Mechanical Properties of 1,4-cis-polybutadiene Melts

2012 ◽  
Vol 1424 ◽  
Author(s):  
Canan Atilgan ◽  
Ibrahim Inanc ◽  
Ali Rana Atilgan
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Bulk Modulus ◽  
Residence Time ◽  
Van Der Waals ◽  
Interaction Strength ◽  
Polymeric Materials ◽  
Van Der Waals Interactions ◽  
Increasing Trend ◽  
Dynamics Simulations

ABSTRACTUsing molecular dynamics simulations, we have investigated the effect of embedding nanoclusters of radius 3-7 Å on the dynamical and mechanical properties of 1,4-cispolybutadiene melts. To see the effect of polymer-nanocluster interaction strength on the bulk modulus, the van der Waals interactions (vdW) between the polymer chain and nanocluster have been varied from weak to very stong while keeping polymer-polymer and nanoclusternanocluster interactions constant. The modulus depends on the interaction strength, but not on nanocluster size. Residence time of chains on the surface of the nanocluster (τr) has an increasing trend that reaches to a plateau as the vdW strength is increased. τr also doubles from 100 ps to 200 ps as the nanocluster size is increased from 3 to 7 Å. Our findings give clues on how the properties of polymeric materials may be controlled by nanoparticles of different chemistry and size.

van der Waals interactions are critical in Car-Parrinello molecular dynamics simulations of porphyrin-fullerene dyads

2015 ◽  
Vol 36 (9) ◽  
pp. 612-621 ◽  
Author(s):  
Topi Karilainen ◽  
Oana Cramariuc ◽  
Mikael Kuisma ◽  
Kirsi Tappura ◽  
Terttu I. Hukka
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Van Der Waals ◽  
Van Der Waals Interactions ◽  
Dynamics Simulations

Van der Waals Attraction and Coalescence of Aqueous Salt Nanodroplets

2003 ◽  
Vol 68 (12) ◽  
pp. 2283-2291 ◽  
Author(s):  
Pavel Jungwirth ◽  
Victoria Buch
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Size Effects ◽  
Relative Velocity ◽  
Van Der Waals ◽  
Van Der Waals Interactions ◽  
Van Der Waals Attraction ◽  
Dynamics Simulations ◽  
Precipitation Modeling

Collisions of aqueous salt nanodroplets at zero initial relative velocity are investigated by means of molecular dynamics simulations. The character of the van der Waals interactions, which bring the droplets together and cause coalescence, is described in detail, and the parameters of the droplet-droplet potential are extracted from the collisional trajectories. Concentration and size effects, together with implications for cloud and precipitation modeling are discussed.

Gauging van der Waals interactions in aqueous solutions of 2D MOFs: when water likes organic linkers more than open-metal sites

2021 ◽  
Vol 23 (4) ◽  
pp. 3135-3143
Author(s):  
Mohammad R. Momeni ◽  
Zeyu Zhang ◽  
David Dell'Angelo ◽  
Farnaz A. Shakib
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solutions ◽  
Molecular Dynamics Simulations ◽  
Van Der Waals ◽  
Van Der Waals Interactions ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Layered Architecture ◽  
Open Metal Sites ◽  
Dynamics Simulations

Periodic quantum mechanical calculations combined with classical molecular dynamics simulations are employed to probe stability of layered architecture of 2D MOFs and show how stability and conductivity are affected by the nature of organic linkers.

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