New-Generation Amber United-Atom Force Field

Yang, Lijiang; Tan, Chun Hu; Hsieh, Meng Juei; Wang, Junmei; Duan, Yong; Cieplak, Piotr; Caldwell, James W.; Kollman, Peter A.; Luo, Ray

doi:10.1021/jp060163v

Cited by 179 publications

(147 citation statements)

References 36 publications

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“…Gasteiger charges were calculated and added for the atoms in the ligand using Autodock Tools (20). The protein model was prepared for docking by merging nonpolar hydrogens into groups for the Kollman united atom force field (28) and adding Kollman charges and Stouten desolvation terms for each atom. Docking was performed by using Autodock 3.02 (29).…”

Section: Methodsmentioning

confidence: 99%

Embedded cholesterol in the nicotinic acetylcholine receptor

Brannigan

Hénin

Law

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

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The nicotinic acetylcholine receptor (nAChR) is a cation-selective channel central to both neuronal and muscular processes and is considered the prototype for ligand-gated ion channels, motivating a structural determination effort that spanned several decades [Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol 346:967-989]. Purified nAChR must be reconstituted in a mixture containing cholesterol to function. Proposed modes of interaction between cholesterol and the protein range from specific binding to indirect membranemediated mechanisms. However, the underlying cause of nAChR sensitivity to cholesterol remains controversial, in part because the vast majority of functional studies were conducted before a medium resolution structure was reported. We show that the nAChR contains internal sites capable of containing cholesterol, whose occupation stabilizes the protein structure. We detect sites at the protein-lipid interface as conventionally predicted from functional data, as well as deeply buried sites that are not usually considered. Molecular dynamics simulations reveal that occupation of both superficial and deeply buried sites most effectively preserves the experimental structure; the structure collapses in the absence of bound cholesterol. In particular, we find that bound cholesterol directly supports contacts between the agonist-binding domain and the pore that are thought to be essential for activation of the receptor. These results likely apply to those other ion channels within the Cys-loop superfamily that depend on cholesterol, such as the GABA receptor.protein-lipid interaction ͉ ligand-gated ion channel ͉ cys loop receptor C ritical for memory and cognition, the nAChR is implicated in neurological disorders (1), addiction (2, 3), and the mechanism of anesthetics (4). Early efforts to reconstitute the nAChR noted that cholesterol as well as charged lipids (such as phosphatidic acid) are required for proper function (5). Proposed mechanisms for the role of cholesterol in nAChR function fall into two general types: indirect and direct. Indirect mechanisms are those in which a cholesterol-induced change in fluid or elastic properties of the lipid bilayer modulates the protein behavior. Although early studies (6, 7) indicated that current flow through the channel is insensitive to bilayer fluid properties, more recent studies (8, 9) have proposed that this result depends on the choice of order parameters. The direct mechanism requires cholesterol binding to the nAChR and effecting structural and/or dynamic changes. Proponents of this theory have determined that (i) cholesterol molecules in proximity to the protein exchange very slowly with the bulk lipid bilayer (10) (electron spin resonance difference spectroscopy); (ii) cholesterol accesses sites on the protein that cannot be occupied by phospholipids (11) (fluorescence quenching); and (iii) some cholesterol bound to the nAChR interacts with the phospholipids in the surrounding bilayer (12) (substit...

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Section: Methodsmentioning

confidence: 99%

Embedded cholesterol in the nicotinic acetylcholine receptor

Brannigan

Hénin

Law

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

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“…Turning to the Lennard-Jones (LJ) parameters σ i and ǫ entering the last term of eq 1, nine atom types were first identified (i. e. chemically equivalent atoms sharing the same parameters, see Tables 1 and 2) and their initial values was set to the one found in literature references. 43,[47][48][49] As it is customarily done, 42,50 the atomic charges q were derived by fitting the molecular electrostatic potential obtained by quantum chemistry calculations. For this purpose the PBE0-D3(BJ)/def2-TZVP model chemistry was adopted, [51][52][53][54][55] with numerical thresholds systematically increased with respect to defaults, and dispersion corrections -D3(BJ), 56 because as we have reported recently, it shows good all-around performances for some of the compounds studied here, as well as for some emitters exhibiting thermally activated delayed fluorescence (see reference 34 for further details).…”

Section: 38mentioning

confidence: 99%

Cost-Effective Force Field Tailored for Solid-Phase Simulations of OLED Materials

Moral

Son

Sancho‐García

et al. 2015

J. Chem. Theory Comput.

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A united atom force field is empirically derived by minimizing the difference between experimental and simulated crystal cells and melting temperatures for eight compounds representative of organic electronic materials used in OLEDs and other devices: biphenyl, carbazole, fluorene,9, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ture also for two larger compounds employed as hosts in phosphorescent and thermally activated delayed fluorescence OLEDs:The good performances of the force field, coupled to the large computational saving granted by the united atom approximation, make it an ideal choice for the simulation of the morphology of emissive layers for OLED materials in crystalline or glassy phases.

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“…The systems were then subjected to MD simulations using the GROMACS simulation package 4.5.5 [37] and applying the AMBER03 [38] force field. The G4 structures prepared in MOE were inserted in a cubic box, with no less than 1 nm between the G4 and the simulation box edge.…”

Section: Fret Melting Assaysmentioning

confidence: 99%

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

et al. 2013

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G‐quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2‐b]quinolines mono‐, di‐, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5‐methyl or a 7‐carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7‐(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter‐G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c‐Kit2, 10‐fold selectivity for G4 over duplex DNA, and 100‐fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.

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New-Generation Amber United-Atom Force Field

Cited by 179 publications

References 36 publications

Embedded cholesterol in the nicotinic acetylcholine receptor

Embedded cholesterol in the nicotinic acetylcholine receptor

Cost-Effective Force Field Tailored for Solid-Phase Simulations of OLED Materials

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

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