Structural Effects of Cation Binding to DPPC Monolayers

Ions at the two sides of the plasma membrane maintain the transmembrane potential, participate in signaling, and affect the properties of the membrane itself. The extracellular leaflet is particularly enriched in phosphatidylcholine lipids an under the influence of Na+, Ca2+, and Cl− ions. In this work, we combined molecular dynamics simulations performed using state-of-the-art models with vibrational sum frequency generation (VSFG) spectroscopy to study the effects of these key ions on the structure of dipalmitoylphosphatidylcholine. We used lipid monolayers as a proxy for membranes, as this approach enabled a direct comparison between simulation and experiment. We find that the effects of Na+ are minor. Ca2+, on the other hand, strongly affects the lipid head group conformations and induces a tighter packing of lipids, thus promoting the liquid condensed phase. It does so by binding to both the phosphate and carbonyl oxygens via direct and water-mediated binding modes, the ratios of which depend on the monolayer packing. Clustering analysis performed on simulation data revealed that changes in area per lipid or CaCl2 concentration both affect the head group conformations, yet their effects are anti-correlated. Cations at the monolayer surface also attract Cl−, which at large CaCl2 concentrations penetrates deep to the monolayer. This phenomenon coincides with a radical change in the VSFG spectra of the phosphate group, thus indicating the emergence of a new binding mode.

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Structural Effects of Cation Binding to DPPC Monolayers

10.26434/chemrxiv.12894962.v1 ◽

2020 ◽

Author(s):

Matti Javanainen ◽

Wei Hua ◽

Ondrej Tichacek ◽

Pauline Delcroix ◽

Lukasz Cwiklik ◽

...

Keyword(s):

Radical Change ◽

Binding Mode ◽

Cation Binding ◽

Head Group ◽

Binding Modes ◽

Sum Frequency ◽

Area Per Lipid ◽

Simulation And Experiment ◽

Lipid Head Group ◽

Dynamics Simulations

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Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽

10.3390/biom8030061 ◽

2018 ◽

Vol 8 (3) ◽

pp. 61 ◽

Cited By ~ 9

Author(s):

Fernando Prieto-Martínez ◽

José Medina-Franco

Keyword(s):

Kinase Inhibitors ◽

Binding Mode ◽

Binding Modes ◽

Ligand Interaction ◽

Bet Inhibitors ◽

Protein Ligand Interaction ◽

Brd4 Inhibition ◽

Dynamics Simulations ◽

Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

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The structure of a valinomycin–hexaaquamagnesium trifluoromethanesulfonate compound

Acta Crystallographica Section C Structural Chemistry ◽

10.1107/s2053229616010676 ◽

2016 ◽

Vol 72 (8) ◽

pp. 627-633

Author(s):

Megumi Fujita ◽

Amaan M. Kazerouni ◽

John Bacsa

Keyword(s):

Hydrogen Bonds ◽

Metal Binding ◽

Binding Mode ◽

Cation Binding ◽

Acetonitrile Solution ◽

Binding Modes ◽

Carbonyl Groups ◽

Amide Hydrogen ◽

Amide Carbonyl

Valinomycin is a naturally occurring cyclic dodecadepsipeptide with the formulacyclo-[D-HiVA→L-Val →L-LA→L-Val]3(D-HiVA is D-α-hydroxyisovaleic acid, Val is valine and LA is lactic acid), which binds a K+ion with high selectively. In the past, several cation-binding modes have been revealed by X-ray crystallography. In the K+, Rb+and Cs+complexes, the ester O atoms coordinate the cation with a trigonal antiprismatic geometry, while the six amide groups form intramolecular hydrogen bonds and the network that is formed has a bracelet-like conformation (Type 1 binding). Type 2 binding is seen with the Na+cation, in which the valinomycin molecule retains the bracelet conformation but the cations are coordinated by only three ester carbonyl groups and are not centrally located. In addition, a picrate counter-ion and a water molecule is found at the center of the valinomycin bracelet. Type 3 binding is observed with divalent Ba2+, in which two cations are incorporated, bridged by two anions, and coordinated by amide carbonyl groups, and there are no intramolecular amide hydrogen bonds. In this paper, we present a new Type 4 cation-binding mode, observed in valinomycin hexaaquamagnesium bis(trifluoromethanesulfonate) trihydrate, C54H90N6O18·[Mg(H2O)6](CF3SO3)2·3H2O, in which the valinomycin molecule incorporates a whole hexaaquamagnesium ion, [Mg(H2O)6]2+,viahydrogen bonding between the amide carbonyl groups and the hydrate water H atoms. In this complex, valinomycin retains the threefold symmetry observed in Type 1 binding, but the amide hydrogen-bond network is lost; the hexaaquamagnesium cation is hydrogen bonded by six amide carbonyl groups.1H NMR titration data is consistent with the 1:1 binding stoichiometry in acetonitrile solution. This new cation-binding mode of binding a whole hexaaquamagnesium ion by a cyclic polypeptide is likely to have important implications for the study of metal binding with biological models under physiological conditions.

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Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102813118 ◽

2021 ◽

Vol 118 (32) ◽

pp. e2102813118

Author(s):

Heng Liu ◽

R. N. V. Krishna Deepak ◽

Anna Shiriaeva ◽

Cornelius Gati ◽

Alexander Batyuk ◽

...

Keyword(s):

Inflammatory Responses ◽

D2 Receptor ◽

Binding Mode ◽

Lipid Binding ◽

Prostaglandin D2 ◽

Polar Group ◽

Binding Modes ◽

Binding Pockets ◽

Dynamics Simulations ◽

G Protein Coupled

Prostaglandin D2 (PGD2) signals through the G protein–coupled receptor (GPCR) CRTH2 to mediate various inflammatory responses. CRTH2 is the only member of the prostanoid receptor family that is phylogenetically distant from others, implying a nonconserved mechanism of lipid action on CRTH2. Here, we report a crystal structure of human CRTH2 bound to a PGD2 derivative, 15R-methyl-PGD2 (15mPGD2), by serial femtosecond crystallography. The structure revealed a “polar group in”–binding mode of 15mPGD2 contrasting the “polar group out”–binding mode of PGE2 in its receptor EP3. Structural comparison analysis suggested that these two lipid-binding modes, associated with distinct charge distributions of ligand-binding pockets, may apply to other lipid GPCRs. Molecular dynamics simulations together with mutagenesis studies also identified charged residues at the ligand entry port that function to capture lipid ligands of CRTH2 from the lipid bilayer. Together, our studies suggest critical roles of charge environment in lipid recognition by GPCRs.

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Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates

Antibodies ◽

10.3390/antib7030025 ◽

2018 ◽

Vol 7 (3) ◽

pp. 25 ◽

Cited By ~ 5

Author(s):

Mingzhen Zhang ◽

Jie Zheng ◽

Ruth Nussinov ◽

Buyong Ma

Keyword(s):

Dynamic Properties ◽

Binding Mode ◽

Single Domain ◽

Binding Modes ◽

Single Domain Antibody ◽

Domain Antibody ◽

Ad Prevention ◽

Dynamics Simulations ◽

Β Sheet ◽

Complementarity Determining Region

Aβ is the toxic amyloid polypeptide responsible for Alzheimer’s disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-Aβ recognition complexes to get insights into their structural and dynamic properties and gammabody-Aβ recognitions. Among many heterogeneous binding modes, we focused on two gammabody-Aβ recognition scenarios: recognition through Aβ β-sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted Aβ sequence to interact with the Aβ fibril, while CDR1/CDR2 loops have very little contact. The gammabody-Aβ complexes with backbone binding mode are more stable, explaining the gammabody’s specificity towards the C-terminal Aβ sequence.

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Effects of the Nonimmobilizer Hexafluroethane on the Model Membrane Dimyristoylphosphatidylcholine

Anesthesiology ◽

10.1097/00000542-200210000-00016 ◽

2002 ◽

Vol 97 (4) ◽

pp. 848-855 ◽

Cited By ~ 15

Author(s):

Laure Koubi ◽

Mounir Tarek ◽

Sanjoy Bandyopadhyay ◽

Michael L. Klein ◽

Daphna Scharf

Keyword(s):

Physical Properties ◽

Lipid Bilayer ◽

Md Simulations ◽

Model Membrane ◽

Head Group ◽

Clinical Effects ◽

Equilibrium Configurations ◽

Area Per Lipid ◽

Lipid Head Group ◽

Chain Conformations

Background Nonimmobilizers are agents that lack anesthetic properties, although their chemical structure is very similar to known anesthetics. The primary action site of both agents, whether at the membrane or target protein level, is still a matter of debate. However, increasing evidence points to the distinct modifications of the membrane physical properties that such agents induce. Such modification may play a role in the mechanism of anesthesia, and may therefore be related to the differences in their clinical behavior. Methods Molecular dynamics (MD) computer simulations have been used to investigate the distribution of a nonimmobilizer, hexafluroethane (HFE, C(2)F(6)), in a lipid membrane. The biologically relevant liquid-crystal phase of a hydrated dimyristoyl phosphatidyl choline (DMPC) bilayer was used as a membrane model. Two MD simulations corresponding to HFE mole fractions of 6% and 25% have been performed at room temperature and constant ambient pressure, for a duration of 2 nanoseconds each. Results The equilibrium configurations of HFE in the bilayer show that the nonimmobilizer molecules are evenly distributed along the lipid hydrocarbon chains with a slight preference for the bilayer center. This partitioning induces an expansion of the bilayer thickness and a lateral contraction of the membrane (decrease of the area per lipid). The presence of HFE has essentially no effect on the lipid acyl chain conformations in agreement with nuclear magnetic resonance (NMR) measurements of the chain order parameters. The partitioning of the nonimmobilizer does not influence the orientation of the lipid head-group dipole moment. Conclusions The modifications induced by the presence of the nonimmobilizer HFE on a model membrane are distinct from those previously found for halothane (CF(3)CHBrCl), its anesthetic analogue, and appear to result from different distributions in the lipid bilayer. The results of the MD simulations show that (1) the changes in the average area per lipid and in the membrane thickness are opposite for the two agents and (2) HFE induces no change in the lipid head-group orientation, in contrast to halothane. These different effects (1) on the physical properties of the lipid bilayer and (2) on the electrostatic properties of the membrane-water interface may be linked to different clinical effects, and thus might contribute to the mechanism of general anesthesia.

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Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR

10.1101/500157 ◽

2018 ◽

Author(s):

Hovakim Grabski ◽

Susanna Tiratsuyan

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Biofilm Formation ◽

Principal Component ◽

Binding Mode ◽

Machine Learning Techniques ◽

Hydroxyl Group ◽

Binding Modes ◽

And Cluster Analysis ◽

Dynamics Simulations

Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.

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Computational Studies of Substrate Transport and Specificity in a Phospholipid Flippase

10.1101/2020.06.24.169771 ◽

2020 ◽

Author(s):

Yong Wang ◽

Joseph A Lyons ◽

Milena Timcenko ◽

Bert L. de Groot ◽

Poul Nissen ◽

...

Keyword(s):

Atp Hydrolysis ◽

Head Group ◽

Outer Leaflet ◽

Type Iv ◽

Lipid Head Group ◽

Dynamics Simulations ◽

Phospholipid Distribution ◽

Phospholipid Transport ◽

P Type ◽

Insight Into

AbstractType-IV P-type ATPases are lipid flippases which help maintain asymmetric phospholipid distribution in eukaryotic membranes by using ATP hydrolysis to drive unidirectional translocation of phospholipid substrates. Recent Cryo-EM and crystal structures have provided a detailed view of flippases, and we here use molecular dynamics simulations of the yeast flippase Drs2p:Cdc50p in an outward open conformation to study the first steps of phospholipid transport. Our simulations show phospholipid binding to a groove and subsequent movement towards the centre of the membrane, and reveal a preference for phosphatidylserine lipids. We find that the lipid head group stays solvated in the groove while the lipid tails stay in the membrane during the (half) transport event. The flippase also induces deformation and thinning of the outer leaflet. Together, our simulations provide insight into substrate binding to lipid flippases and suggest that multiple sites and steps in the functional cycle contribute to substrate selectivity.

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A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes

International Journal of Molecular Sciences ◽

10.3390/ijms20081970 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1970 ◽

Cited By ~ 4

Author(s):

Christian A. Söldner ◽

Anselm H. C. Horn ◽

Heinrich Sticht

Keyword(s):

Ligand Binding ◽

Pharmaceutical Research ◽

Binding Mode ◽

Model Systems ◽

Binding Modes ◽

Enhanced Sampling ◽

Conformational Ensembles ◽

Precise Knowledge ◽

Preferential Binding ◽

Dynamics Simulations

G protein-coupled receptors (GPCRs) are a main drug target and therefore a hot topic in pharmaceutical research. One important prerequisite to understand how a certain ligand affects a GPCR is precise knowledge about its binding mode and the specific underlying interactions. If no crystal structure of the respective complex is available, computational methods can be used to deduce the binding site. One of them are metadynamics simulations which have the advantage of an enhanced sampling compared to conventional molecular dynamics simulations. However, the enhanced sampling of higher-energy states hampers identification of the preferred binding mode. Here, we present a novel protocol based on clustering of multiple walker metadynamics simulations which allows identifying the preferential binding mode from such conformational ensembles. We tested this strategy for three different model systems namely the histamine H1 receptor in combination with its physiological ligand histamine, as well as the β 2 adrenoceptor with its agonist adrenaline and its antagonist alprenolol. For all three systems, the proposed protocol was able to reproduce the correct binding mode known from the literature suggesting that the approach can more generally be applied to the prediction of GPCR ligand binding in future.

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Predicting stable binding modes from simulated dimers of the D76N mutant of β2-microglobulin

10.1101/2021.07.14.452361 ◽

2021 ◽

Author(s):

Nuno F. B. Oliveira ◽

Filipe E. P. Rodrigues ◽

João N. M. Vitorino ◽

Rui J.S. Loureiro ◽

Patrícia FN Faísca ◽

...

Keyword(s):

Hydrophobic Interactions ◽

Early Stage ◽

Structural Rearrangement ◽

Binding Mode ◽

Protein Docking ◽

Interfacial Region ◽

Binding Modes ◽

Limited Growth ◽

C Terminus ◽

Dynamics Simulations

The D76N mutant of the beta-2-microgobulin protein is a biologically motivated model system to study protein aggregation. There is strong experimental evidence, supported by molecular simulations, that D76N populates a highly dynamic conformation (which we originally named I2) that exposes aggregation-prone patches as a result of the detachment of the two terminal regions. Here, we use Molecular Dynamics simulations to study the stability of an ensemble of dimers of I2 generated via protein-protein docking. MM-PBSA calculations indicate that within the ensemble of investigated dimers the major contribution to interface stabilization at physiological pH comes from hydrophobic interactions between apolar residues. Our structural analysis also reveals that the interfacial region associated with the most stable binding modes are particularly rich in residues pertaining to both the N- and C-terminus, as well residues from the BC- and DE-loops. On the other hand, the less stable interfaces are stabilized by intermolecular interactions involving residues from the CD- and EF-loops. By focusing on the most stable binding modes, we used a simple geometric rule to propagate the corresponding dimer interfaces. We found that, in the absence of any kind of structural rearrangement occurring at an early stage of the oligomerization pathway, some interfaces drive a self-limited growth process, while others can be propagated indefinitely allowing the formation of long, polymerized chains. In particular, the interfacial region of the most stable binding mode reported here falls in the class of self-limited growth.

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