Electrostatics and diffusion of molecules in solution: simulations with the University of Houston Brownian dynamics program

Davis, Morris; Madura, Jeffry D.; Luty, Brock A.; McCammon, J. Andrew

doi:10.1016/0010-4655(91)90094-2

Cited by 462 publications

(398 citation statements)

References 21 publications

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“…Structures and models were checked and compared by using PROCHECK (37) and WHATCHECK (38). Before running simulations, side-chain ionization states were adjusted to match the results of pK a calculations, performed as described (39), using UHBD (40) to calculate free energy differences between ionized and unionized side chains of the protein. Protonation states were then checked manually to assure no inappropriate results caused by the approximations of the method (41), and the H-bonding network was not optimized before the calculation.…”

Section: Methodsmentioning

confidence: 99%

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

Law

Henchman

McCammon

2005

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

134

142

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The nicotinic acetylcholine receptor is a well characterized ligandgated ion channel, yet a proper description of the mechanisms involved in gating, opening, closing, ligand binding, and desensitization does not exist. Until recently, atomic-resolution structural information on the protein was limited, but with the production of the x-ray crystal structure of the Lymnea stagnalis acetylcholine binding protein and the EM image of the transmembrane domain of the torpedo electric ray nicotinic channel, we were provided with a window to examine the mechanism by which this channel operates. A 15-ns all-atom simulation of a homology model of the homomeric human ␣7 form of the receptor was conducted in a solvated palmitoyl-2-oleoyl-sn-glycerol-phosphatidylcholine bilayer and examined in detail. The receptor was unliganded. The structure undergoes a twist-to-close motion that correlates movements of the C loop in the ligand binding domain, via the ␤10-strand that connects the two, with the 10°rotation and inward movement of two nonadjacent subunits. The Cys loop appears to act as a stator around which the ␣-helical transmembrane domain can pivot and rotate relative to the rigid ␤-sheet binding domain. The M2-M3 loop may have a role in controlling the extent or kinetics of these relative movements. All of this motion, along with essential dynamics analysis, is suggestive of the direction of larger motions involved in gating of the channel.T he nicotinic acetylcholine receptor is one of the best-studied ligand-gated ion channels (LGICs) (1). It has been found to have a role in a wide range of pathological conditions and diseases including epilepsy (2), schizophrenia (3), Alzheimer's (4), Parkinson's (5), neuromuscular diseases (6), inflammation (7), nicotine addiction (8), and addiction to other drugs such as alcohol (9) and cocaine (10), as well as a role in anesthetic action (11). The nicotinic acetylcholine receptor is a member of a superfamily of pentameric receptors that include the serotonin (excitory), GABA, and glycine (inhibitory) receptors that are all involved in the transmission and modification of electrical signals in excitory cells. The family is known as the Cys-loop LGIC family, because of a conserved pair of linked cysteines in the N-terminal domain of the receptor (12). Within the superfamily, an array of different nicotinic receptor subunits exists (13,14), making different subunit assemblies possible, for different roles, in different cell types. In all of these receptors, the ligand binds at the interface between the ␣ and other subunits of the ligand binding domain (LBD). This event begins a chain reaction of conformational changes within the receptor that transmits the message of ligand binding to the transmembrane domain (TMD), which then opens to allow the passage of ions through the channel. Although the genetics, kinetics, electrophysiology, and many topological aspects are well characterized for the nicotinic receptor (15, 16), the exact nature of the structural rearrangments involved in activ...

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Section: Methodsmentioning

confidence: 99%

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

Law

Henchman

McCammon

2005

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

134

142

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“…These structures are shown in Fig Analysis of electrostatic contributions to protein-ligand association energy requires that protonation states of their ionizable groups for given solution conditions are determined. The protonation probabilities of titrat-6 able groups in the eIF4E protein and terminal phosphate groups of m 7 GTP, m 7 Gp 4 ligands, corresponding to experimental conditions of the fluorescence titration measurements [24], were calculated as described in detail elsewhere [30,31], using the University of Houston Brownian Dynamics program (UHBD) [32,33]. For the purpose of predicting titration equilibria, all hydrogens were added and optimised with respect to their positions using CHARMM.…”

Section: Computational Proceduresmentioning

confidence: 99%

Poisson–Boltzmann model analysis of binding mRNA cap analogues to the translation initiation factor eIF4E

Szklarczyk

Zuberek

Antosiewicz

2009

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractThe electrostatic free energy of binding of two analogues of the 5'-mRNA cap, differing in size and electric charge, to the wild type and mutated eukaryotic initiation factor eIF4E was computed using the finite difference solutions to the Poisson-Boltzmann equation. Two definitions of the solute-solvent dielectric boundary were used: van der Waals model, solvent exclusion (SE) model. The computed electrostatic energies were supplemented by estimations of the non polar and entropic contributions. A comparison with experimental data for the investigated systems was done. It appears that the SE model with additional contribution fits experimental findings better than the van der Waals model does.

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“…The electrostatic potentials were calculated by numerically solving the finite difference linearized PB equation using an incomplete Cholesky preconditioned conjugate gradient method as implemented in the University of Houston Brownian Dynamics (UHBD) program, version 4.0 (Davis et al, 1990). The OPLS parameter set (Jorgensen & Tirado-Rives, 1988), with the radii of hydrogen atoms set to 1.2 A, was used to assign atomic radii and partial charges.…”

Section: Electrostatics Calculations Acknowledgmentsmentioning

confidence: 99%

Receptor binding properties of four‐helix‐bundle growth factors deduced from electrostatic analysis

et al. 1994

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Hormones of the hematopoietin class mediate signal transduction by binding to specific transmembrane receptors. Structural data show that the human growth hormone (hGH) forms a complex with a homodimeric receptor and that hGH is a member of a class of hematopoietins possessing an antiparallel 4-a-helix bundle fold. Mutagenesis experiments suggest that electrostatic interactions may have an important influence on hormonereceptor recognition. In order to examine the specificity of hormone-receptor complexation, an analysis was made of the electrostatic potentials of hGH, interleukin-2 (IL-2), interleukin-4 (IL-4), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the hGH and IL-4 receptors.The binding surfaces of hGH and its receptor, and of IL-4 and its receptor, show complementary electrostatic potentials. The potentials of the hGH and its receptor display approximately 2-fold rotational symmetry because the receptor subunits are identical. In contrast, the potentials of GM-CSF and IL-2 lack such symmetry, consistent with their known high affinity for hetero-oligomeric receptors. Analysis of the electrostatic potentials supports a recently proposed hetero-oligomeric model for a high-affinity IL-4 receptor and suggests a possible new receptor binding mode for G-CSF; it also provides valuable information for guiding structural and mutagenesis studies of signal-transducing proteins and their receptors.

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Electrostatics and diffusion of molecules in solution: simulations with the University of Houston Brownian dynamics program

Cited by 462 publications

References 21 publications

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

Poisson–Boltzmann model analysis of binding mRNA cap analogues to the translation initiation factor eIF4E

Receptor binding properties of four‐helix‐bundle growth factors deduced from electrostatic analysis

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