Cholesterol's aliphatic side chain modulates membrane properties.
Ontology highlight
ABSTRACT:
SUBMITTER: Scheidt HA
PROVIDER: S-EPMC4011182 | biostudies-other | 2013 Dec
REPOSITORIES: biostudies-other
Publications
Cholesterol's aliphatic side chain modulates membrane properties.
Scheidt Holger A HA Meyer Thomas T Nikolaus Jörg J Baek Dong Jae DJ Haralampiev Ivan I Thomas Lars L Bittman Robert R Müller Peter P Herrmann Andreas A Huster Daniel D
Angewandte Chemie (International ed. in English) 20131125 49
The influence of cholesterol's alkyl side chain on membrane properties was studied using a series of synthetic cholesterol derivatives without a side chain or with a branched side chain consisting of 5 to 14 carbon atoms. Cholesterol's side chain is crucial for all membrane properties investigated and therefore essential for the membrane properties of eukaryotic cells. ...[more]
Similar Datasets
Project description:Daphnane diterpenoids were recognized for their extensive range of potent biological activities. In the present study, phytochemical investigation including LC-MS/MS analysis resulted in the identification of five daphnane diterpenoid orthoesters (1-5). Among the five daphnane diterpenoids, two previously unreported compounds, daphnepedunins I and J (2 and 4) were isolated from Daphne pedunculata. The structure of new compounds was elucidated with extensive physicochemical and spectroscopic analyses. Their structure was characterized by the presence of an unusual odd-numbered aliphatic chain connected to an orthoester. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells, and the results indicated that compound 1 showed the most potent anti-HIV activity with an IC50 value of 0.82 nM.
| S-EPMC11365762 | biostudies-literature
Project description:Introduction of an aliphatic side chain to a key position of a novel piperidine-based HDM2 inhibitor scaffold resulted in significant potency gains, enabling further series progression.
| S-EPMC4027732 | biostudies-literature
Project description:Cholesterol is a necessary component and critical regulator of liquid-ordered membrane domains. However, the structural features that determine its unique physicochemical behaviors are not fully understood. In particular, very little is known about the specific functions of the terminal aliphatic chain of cholesterol, as previous studies have focused mainly on the rigid sterol ring structure and its hydroxyl head. In the current work, we used coarse-grained molecular dynamics simulations to investigate the effect of cholesterol aliphatic chain length on the dynamics and structure of coexisting lipid domains. We found that the aliphatic chain has no appreciable effect on phase separation per se, but it significantly affects the rate of cholesterol flip-flop and intermonolayer interaction. These effects are accompanied by changes in domain dynamics, lateral pressure, and interleaflet coupling. Our study provides useful insight into how biological sterols modulate communication between the outer and inner surfaces of the plasma membrane and, therefore, cellular signaling.
| S-EPMC5064870 | biostudies-literature
Project description:Side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), are key regulators of cholesterol homeostasis. New evidence suggests that the alteration of membrane structure by 25-HC contributes to its regulatory effects. We have examined the role of oxysterol membrane effects on cholesterol accessibility within the membrane using perfringolysin O (PFO), a cholesterol-dependent cytolysin that selectively binds accessible cholesterol, as a sensor of membrane cholesterol accessibility. We show that 25-HC increases cholesterol accessibility in a manner dependent on the membrane lipid composition. Structural analysis of molecular dynamics simulations reveals that increased cholesterol accessibility is associated with membrane thinning, and that the effects of 25-HC on cholesterol accessibility are driven by these changes in membrane thickness. Further, we find that the 25-HC antagonist LY295427 (agisterol) abrogates the membrane effects of 25-HC in a nonenantioselective manner, suggesting that agisterol antagonizes the cholesterol-homeostatic effects of 25-HC indirectly through its membrane interactions. These studies demonstrate that oxysterols regulate cholesterol accessibility, and thus the availability of cholesterol to be sensed and transported throughout the cell, by modulating the membrane environment. This work provides new insights into how alterations in membrane structure can be used to relay cholesterol regulatory signals.
| S-EPMC4020583 | biostudies-literature
Project description:The intrinsic conformational preferences of small peptides may provide additional insight into the thermodynamics and kinetics of protein folding. In this study, we explore the underlying energy landscapes of two model peptides, namely, Ac-Ala-NH2 and Ac-Ser-NH2, using geometry-optimization-based tools developed within the context of energy landscape theory. We analyze not only how side-chain polarity influences the structural preferences of the dipeptides, but also other emergent properties of the landscape, including heat capacity profiles, and kinetics of conformational rearrangements. The contrasting topographies of the free energy landscape agree with recent results from Fourier transform microwave spectroscopy experiments, where Ac-Ala-NH2 was found to exist as a mixture of two conformers, while Ac-Ser-NH2 remained structurally locked, despite exhibiting an apparently rich conformational landscape.
| S-EPMC8279551 | biostudies-literature
Project description:The interactions among four amino acid analog pairs (Asn, Ser, Phe, and Val) within the membrane environment were investigated using umbrella sampling molecular dynamics simulations. The results confirm generally expected qualitative trends of preferential association of polar compounds inside the membrane vs preferential interaction of hydrophobic compounds outside the membrane. Furthermore, correlations between amino acid interactions, membrane insertion, and membrane deformations are discussed and a detailed analysis of pair interaction energies is presented. A comparison of the energetics obtained from explicit lipid simulations with those from implicit membrane models reveals significant deviations and an improved parametrization of the heterogeneous dielectric generalized Born implicit model is provided that partially corrects for deficiencies in the implicit membrane model when compared with the new reference data from this study.
| S-EPMC4420737 | biostudies-literature
Project description:Some cellulose derivatives are known to exhibit thermotropic and lyotropic cholesteric liquid crystal (CLC) phases with a visible reflection feature by changing the side chains and mixing with specific solvents, respectively. Although many studies have been reported so far, most of the derivatives have the side chains of linear alkyl groups, but not the bulky phenyl groups. In this report, we synthesized a series of hydroxypropyl cellulose (HPC) derivatives that possessed both linear propionyl esters and bulky (trifluoromethyl)phenyl carbamates in the side chains. The reflection peaks of HPC derivatives shifted to longer wavelengths upon heating due to an increase in the CLC helical pitch. Such thermally induced shifting behavior of the reflection peak was crucially dependent on not only the propionyl esterification degree, but also the substituents in the side chains of HPC derivatives. When the side chains of HPC were chemically modified with both propionyl esters and bulky substituents such as 3,5-bis(trifluoromethyl)phenyl carbamates, the reflection peaks emerged at longer wavelengths at the same temperature. This probably happened because of the steric hindrance of bulky side chains, as supported by the empirical molecular modeling calculation. Although the occupied volumes of (trifluoromethyl)phenyl groups were independent of the CLC phase temperature with visible Bragg reflection, the substituent position, i.e., substituent orientation of trifluoromethyl groups affected the CLC phase temperature. Moreover, we found that the hydrogen bonds between carbamate moieties in the HPC side chains play an important role in the thermally induced shift of reflection peaks.
| S-EPMC6835709 | biostudies-literature
Project description:Histone lysine methyltransferases (KMTs) play an important role in epigenetic gene regulation and have emerged as promising targets for drug discovery. However, the scope and limitation of KMT catalysis on substrates possessing substituted lysine side chains remain insufficiently explored. Here, we identify new unnatural lysine analogues as substrates for human methyltransferases SETD7, SETD8, G9a and GLP. Two synthetic amino acids that possess a subtle modification on the lysine side chain, namely oxygen at the ? position (KO, oxalysine) and nitrogen at the ? position (KN, azalysine) were incorporated into histone peptides and tested as KMTs substrates. Our results demonstrate that these lysine analogues are mono-, di-, and trimethylated to a different extent by trimethyltransferases G9a and GLP. In contrast to monomethyltransferase SETD7, SETD8 exhibits high specificity for both lysine analogues. These findings are important to understand the substrate scope of KMTs and to develop new chemical probes for biomedical applications.
| S-EPMC7726145 | biostudies-literature
Project description:Understanding the energetics of molecular interactions is fundamental to all of the central quests of structural biology including structure prediction and design, mapping evolutionary pathways, learning how mutations cause disease, drug design, and relating structure to function. Hydrogen-bonding is widely regarded as an important force in a membrane environment because of the low dielectric constant of membranes and a lack of competition from water. Indeed, polar residue substitutions are the most common disease-causing mutations in membrane proteins. Because of limited structural information and technical challenges, however, there have been few quantitative tests of hydrogen-bond strength in the context of large membrane proteins. Here we show, by using a double-mutant cycle analysis, that the average contribution of eight interhelical side-chain hydrogen-bonding interactions throughout bacteriorhodopsin is only 0.6 kcal mol(-1). In agreement with these experiments, we find that 4% of polar atoms in the non-polar core regions of membrane proteins have no hydrogen-bond partner and the lengths of buried hydrogen bonds in soluble proteins and membrane protein transmembrane regions are statistically identical. Our results indicate that most hydrogen-bond interactions in membrane proteins are only modestly stabilizing. Weak hydrogen-bonding should be reflected in considerations of membrane protein folding, dynamics, design, evolution and function.
| S-EPMC2734483 | biostudies-literature
Project description:Understanding the structure and dynamics of membrane proteins in their native, hydrophobic environment is important to understanding how these proteins function. EPR spectroscopy in combination with site-directed spin labeling (SDSL) can measure dynamics and structure of membrane proteins in their native lipid environment; however, until now the dynamics measured have been qualitative due to limited knowledge of the nitroxide spin label's intramolecular motion in the hydrophobic environment. Although several studies have elucidated the structural origins of EPR line shapes of water-soluble proteins, EPR spectra of nitroxide spin-labeled proteins in detergents or lipids have characteristic differences from their water-soluble counterparts, suggesting significant differences in the underlying molecular motion of the spin label between the two environments. To elucidate these differences, membrane-exposed ?-helical sites of the leucine transporter, LeuT, from Aquifex aeolicus, were investigated using X-ray crystallography, mutational analysis, nitroxide side chain derivatives, and spectral simulations in order to obtain a motional model of the nitroxide. For each crystal structure, the nitroxide ring of a disulfide-linked spin label side chain (R1) is resolved and makes contacts with hydrophobic residues on the protein surface. The spin label at site I204 on LeuT makes a nontraditional hydrogen bond with the ortho-hydrogen on its nearest neighbor F208, whereas the spin label at site F177 makes multiple van der Waals contacts with a hydrophobic pocket formed with an adjacent helix. These results coupled with the spectral effect of mutating the i ± 3, 4 residues suggest that the spin label has a greater affinity for its local protein environment in the low dielectric than on a water-soluble protein surface. The simulations of the EPR spectra presented here suggest the spin label oscillates about the terminal bond nearest the ring while maintaining weak contact with the protein surface. Combined, the results provide a starting point for determining a motional model for R1 on membrane proteins, allowing quantification of nitroxide dynamics in the aliphatic environment of detergent and lipids. In addition, initial contributions to a rotamer library of R1 on membrane proteins are provided, which will assist in reliably modeling the R1 conformational space for pulsed dipolar EPR and NMR paramagnetic relaxation enhancement distance determination.
| S-EPMC2991438 | biostudies-literature