Search

Farnesyl (Far) and palmitoyl (Pal) anchors play important roles in the traffic of many lipidated proteins. Herein, we show the distinctive interactions and influences of the two lipid modifications on lipid rafts (LRs) and non-raft-like membranes using molecular dynamics simulations. Palmitoyl anchors behave in a more ordered fashion, pack tighter with the lipids of LRs and diffuse at a slower rate than farnesyl anchors in LRs. When interacting with non-raft-like membranes these two types of anchors become less ordered, pack more loosely with lipids, and diffuse at a higher rate. By calculating both the number of contacts per chain and the number of contact atoms per carbon of the two anchors with the lipid components, we found that the palmitoyl chains preferred to associate with the saturated chains of lipids and cholesterol molecules in LRs, while farnesyl chains favored association with saturated chains and unsaturated chains. For non-raft-like membranes, these two lipid anchors had roughly the same preference for the three types of contact lipid chains. Additionally, palmitoyl anchors caused cholesterol to orient more perpendicular to the membrane surface, surrounding lipids to become more ordered, and lipid lateral fluidity to reduce significantly, compared to farnesyl anchors in LRs. By contrast, the POPE and DSPC became much less ordered, cholesterol became more tilted, and lipids became more fluid, when the two types lipid anchors were inserted in non-raft-like membranes. These findings are useful for understanding the traffic mechanisms of lipidated proteins with farnesyl and palmitoyl modifications in cell membranes. [ABSTRACT FROM AUTHOR]

Two conserved histidine residues are located near the mid-point of the conduction channel of ammonium transport proteins. The role of these histidines in ammonia and methylamine transport was evaluated by using a combination of in vivo studies, molecular dynamics (MD) simulation, and potential of mean force (PMF) calculations. Our in vivo results showed that a single change of either of the conserved histidines to alanine leads to the failure to transport methylamine but still facilitates good growth on ammonia, whereas double histidine variants completely lose their ability to transport both methylamine and ammonia. Molecular dynamics simulations indicated the molecular basis of the in vivo observations. They clearly showed that a single histidine variant (H168A or H318A) of AmtB confines the rather hydrophobic methylamine more strongly than ammonia around the mutated sites, resulting in dysfunction in conducting the former but not the latter molecule. PMF calculations further revealed that the single histidine variants form a potential energy well of up to 6 kcal/mol for methylamine, impairing conduction of this substrate. Unlike the single histidine variants, the double histidine variant, H168A/H318A, of AmtB was found to lose its unidirectional property of transporting both ammonia and methylamine. This could be attributed to a greatly increased frequency of opening of the entrance gate formed by F215 and F107, in this variant compared to wild-type, with a resultant lowering of the energy barrier for substrate to return to the periplasm. [ABSTRACT FROM AUTHOR]

Abstract: The inhibition activity of an imidazoline derivative, namely 1-[N,N′-bis(hydroxylethylether)-aminoethyl]-2-stearicimidazoline (HASI) for carbon steel in 5% NaCl saturated Ca(OH)2 solution was investigated using electrochemical measurements in conjunction with Raman and Fourier transform infrared (FTIR) spectroscopy techniques. Quantum chemical calculations and molecular dynamic (MD) simulations were applied to analyze the experimental data and elucidate the adsorption behavior and inhibition mechanism of inhibitor. The results indicate that HASI is an effective inhibitor in protecting carbon steel from corrosion in alkaline chloride solution and acts as a cathodic type inhibitor with the dominant suppression of cathodic reduction of oxygen. The inhibition behavior of HASI is strongly related to its adsorption activity on carbon steel surface, which leads to an enhancing in the corrosion resistance of carbon steel and a reduction in the corrosion rate. Density functional theory (DFT) calculations suggest that the NN region in imidazoline ring is the most active reaction site for the inhibitor adsorption on metal surface via the donor–acceptor interactions between the lone electron pairs on nitrogen atoms together with the π-electrons of heterocyclic and the vacant d orbital of iron atoms. The adsorption of inhibitor on three typical surfaces (Fe (100), F2O3 (110) and F3O4 (100)) takes nearly parallel to the surface so as to maximize its contact with the surface, as shown as the MD simulations. The experiments incorporating the theoretical calculation and MD simulation can provide an insight into the understanding of interactions between the inhibitor molecules and the carbon steel surfaces. [Copyright &y& Elsevier]

In present study, we set out to investigate the conformation dynamics of Aβ40 and Aβ42 through exploring the impact of intra-molecular interactions on conformation dynamics using equilibrium molecular dynamics simulations. Our 40 microsecond-scale simulations reveal heterogeneous conformation ensembles of Aβ40 and Aβ42 that encompass ~35% β-strand and ~60% unstructured coils. Two conformational states were identified in both alloforms: a collapsed state (CS) that resembles the structural motif of face-to-face hydrophobic clustering in amyloid fibrils, and an extended state (ES) that features the structural characteristics of anti-parallel β-sheets in amyloid oligomers. In Aβ40, the C-terminus remains unstructured and rarely interacts with other parts, thereof the hydrophobic clustering is in loose contact and the peptide assumes ES with high probability. In contrast, the C-terminus of Aβ42 adopts a β-strand structure that strongly interacts with segments E3-R5 and V18-A21. The active association leads to a more compact hydrophobic collapse and refrain the alloform from ES. Based on the structural characterization, we propose that the fibril and oligomer assembly pathways could respectively take off from CS and ES, and their aggregation propensity may be governed by the probability of visiting the corresponding conformational states at the equilibrium. [ABSTRACT FROM AUTHOR]

[Display omitted] • Modified non-bonded interaction energy model was developed to predict co-amorphous. • The model hit 5 new co-amorphous of gefitinib and 4 new co-amorphous of erlotinib. • The proportion of co-former and value of Δ E non-bonded showed a quadratic relationship. • Typical co-amorphous samples exhibited excellent solubility and good stability. Co-amorphous (CA) formulation is a promising strategy to improve the solubility of poorly water-soluble drugs, however, effective prediction of a CA system is a challenge. In this study, a modified non-bonded interaction energy (Δ E non-bonded) model was developed based on 105 solvent-based cases of 13 drugs chosen from the literature to predict CA formation by solvent-based methods using molecular dynamic simulation. With the cut-off value of −3500 kJ·mol−1, the model hit 5 gefitinib CAs and 4 erlotinib CAs, validating its feasibility. The quadratic relationship between co-former proportion (x co-former) and Δ E non-bonded was analyzed using polynomial regression, indicating the x co-former is most likely to render CA when Δ E non-bonded reaches its extreme value. Hydrogen bonds between the NH group of active pharmaceutical ingredient and sulfonamide group of co-former were confirmed experimentally and computationally. Typical CA samples showed remarkable improved solubility (12.1 and 9.3 times) in PBS solution and good physical stability under room conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] • The extracellular domains of GPR110 was solved at 2.9 Å resolution. • Crystal structure reveals atomic details for the domain connections between SEA, HormR, and GAIN domains. • A N-linked glycosylation on N389 is critical for the folding and secretion of GPR110. • Docking of ligand synaptamide on GPR110 shed light on potential activation mechanism. Adhesion G protein-coupled receptors (aGPCRs) play a pivotal role in human immune responses, cellular communication, organ development, and other processes. GPR110 belongs to the aGPCR subfamily VI and was initially identified as an oncogene involved in lung and prostate cancers. GPR110 contains tandem adhesion domains at the extracellular region that mediate inter-cellular signaling. However, the structural organization and signaling mechanism for these tandem domains remain unclear. Here, we report the crystal structure of a GPR110 fragment composing the SEA, HormR, and GAIN domains at 2.9 Å resolution. The structure together with MD simulations reveal rigid connections between these domains that are stabilized by complementary interfaces. Strikingly, we found N-linked carbohydrates attached to N389 of the GAIN domain form extensive contacts with the preceding HormR domain. These interactions appear to be critical for folding, as removal of the glycosylation site greatly decreases expression of the GPR110 extracellular fragment. We further demonstrate that the ligand synaptamide fits well within the hydrophobic pocket occupied by the Stachel peptide in the rest state. This suggests that the agonist may function by removing the Stachel peptide which in turn redocks to the orthosteric pocket for receptor activation. Taken together, our structural findings and analyses provide novel insights into the activation mechanism for aGPCRs. [ABSTRACT FROM AUTHOR]

Previous molecular dynamics (MD) simulations of ion-lipid interactions have focused on pure phospholipid bilayers. Many functional microdomains in membranes have a complex composition of cholesterol and phospholipids. Here, we reveal the distinctiveness of the interactions and the effects of the ions on a cholesterol-rich bilayer by performing MD simulations of a cholesterol-rich bilayer with a Na + /K + mixture or a Na + /K + /Ca 2+ /Mg 2+ mixture. The simulations reveal that Ca 2+ maintains its dominant role in the interaction with the cholesterol-rich bilayer, but the binding affinity of Mg 2+ to the cholesterol-rich bilayer is even weaker than the affinities of Na + and K + , whereas its interaction with pure phospholipid bilayers is strong and is only slightly weaker than that of Ca 2+ . Additionally, it was found that the presence of additional divalent cations induces the headgroups of phospholipids to be more perpendicular to the membrane surface, reducing the lateral movement of lipids and slightly altering the ordering and packing of the cholesterol-rich bilayer, different from divalent cations, which strongly influence that ordering and packing of pure phospholipid bilayers. Therefore, this study indicates that cholesterol in the membrane could affect the interactions between membrane and cations. The findings could be helpful in understanding the biological processes relevant to regulation of cations in cholesterol-rich regions. [ABSTRACT FROM AUTHOR]

Cholesterol, an abundant membrane component in both lipidrafts and caveolae of cell membrane, plays a crucial role in regulatingthe function and organization of various G-protein coupled receptors(GPCRs). However, the underlying mechanism for cholesterol-GPCR interactionis still unclear. To this end, we performed a series of microsecondmolecular dynamics (MD) simulations on β2-adrenergicreceptor (β2AR) in the presence and absence of cholesterolmolecules in the POPC bilayer. The unbiased MD simulation on the systemwith cholesterols reveals that cholesterol molecules can spontaneouslydiffuse to seven sites on the β2AR surfaces, threein the extracellular leaflet (e1–e3) and four in the intracellularleaflet (i1, i2, i4, and i5). The MD simulation identifies three cholesterol-bindingsites (i2, e2, and e3) that are also observed in the crystal structuresof several GPCRs. Cholesterol binding to site e1 lock Trp3137.40into a certain conformation that may facilitate ligand–receptorbinding, and cholesterol binding to site i2 provides a structuralsupport for the reported cholesterol-mediate dimeric form of β2AR (PDB code 2RH1). In addition, both competitive and cooperativeeffects between cholesterols and phospholipids in binding to β2AR were observed in our MD simulations. Together, these resultsprovide new insights into cholesterol–GPCR interactions. [ABSTRACT FROM AUTHOR]

Ion mixtures are prevalent in both cytosol and the exteriorofa plasma membrane with variable compositions and concentrations. Althoughabundant MD simulations have been performed to study the effects ofsingle ion species on the structures of lipid bilayers, our understandingof the influence of the ion mixture on membranes is still limited;for example, the competition mechanism of different ions in bindingwith lipids is not clearly addressed yet. Here, microsecond MD simulationswere carried out to study the effects of the mixtures of Ca2+, Mg2+, Na+, and K+ions on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) bilayer. It has beenrevealed that the binding efficiency of these ions with POPG lipidsis in the following order, Ca2+> Mg2+>Na+> K+. The binding free energy of Ca2+to the lipid bilayer is ∼−4.0 kcal/mol, whichis muchlower than those of other ions. This result explains why the effectsof the ion mixture on membranes are particularly sensitive to theconcentration of calcium. The on-rates of different ions do not havea large difference, while the off-rate of Ca2+is 2–3orders of magnitude smaller than those of the others. Therefore, thestrongest binding affinity of Ca2+is mainly determinedby its smallest off-rate. In addition, our study suggests that thestructure of the lipid bilayer is influenced dominantly by the concentrationof Ca2+ions. The simulation results also provide a goodexplanation for a variety of biological processes relevant to Ca2+and Mg2+regulations, such as membrane fusion. [ABSTRACT FROM AUTHOR]

Deafness non-syndromic autosomal dominant 2 (DFNA2) is characterized by symmetric, predominantly high-frequency sensorineural hearing loss that is progressive across all frequencies. The disease is associated with variants of a potassium voltage-gated channel subfamily Q member 4 gene, KCNQ4 (Kv7.4). Here, we studied nine recently identified Kv7.4 variants in DFNA2 pedigrees, including V230E, E260K, D262V, Y270H, W275R, G287R, P291L, P291S and S680F. We proved that the variant S680F did not alter the channel function while the other eight variants resulted in function deficiencies. We further proved that the two variants E260K and P291S showed reduced cell membrane expressions while the other seven variants showed moderate cell surface expressions. Thus, trafficking deficiency is not a common mechanism underlying channel dysfunction. Next, we studied two variants, V230E and G287R, using molecular dynamics simulation. We showed that V230E stabilized Kv7.4 channel in the closed state by forming an additional hydrogen bond with a basic residue K325, while G287R distorted the selectivity filter and blocked the pore region of Kv7.4 channel. Moreover, by co-expressing wild-type (WT) and variant proteins in vitro , we demonstrated that the heterogeneous Kv7.4 channel currents were reduced compared to the WT channel currents and the reduction could be rescued by a Kv7.4 opener retigabine. Our study provided the underlying mechanisms and suggested a potential alternative therapeutic approach for DFNA2. • Kv7.4 variants without trafficking deficiency induce channel dysfunction. • Molecular dynamics simulation explains Kv7.4 variants induced channel dysfunction. • Retigabine rescues hearing loss related heterogeneous Kv7.4 channel function. [ABSTRACT FROM AUTHOR]

In present study, we set out to investigate the conformation dynamics of Aβ40 and Aβ42 through exploring the impact of intra-molecular interactions on conformation dynamics using equilibrium molecular dynamics simulations. Our 40 microsecond-scale simulations reveal heterogeneous conformation ensembles of Aβ40 and Aβ42 that encompass ~35% β-strand and ~60% unstructured coils. Two conformational states were identified in both alloforms: a collapsed state (CS) that resembles the structural motif of face-to-face hydrophobic clustering in amyloid fibrils, and an extended state (ES) that features the structural characteristics of anti-parallel β-sheets in amyloid oligomers. In Aβ40, the C-terminus remains unstructured and rarely interacts with other parts, thereof the hydrophobic clustering is in loose contact and the peptide assumes ES with high probability. In contrast, the C-terminus of Aβ42 adopts a β-strand structure that strongly interacts with segments E3-R5 and V18-A21. The active association leads to a more compact hydrophobic collapse and refrain the alloform from ES. Based on the structural characterization, we propose that the fibril and oligomer assembly pathways could respectively take off from CS and ES, and their aggregation propensity may be governed by the probability of visiting the corresponding conformational states at the equilibrium. [ABSTRACT FROM AUTHOR]