Molecular dynamics for very large systems on massively parallel computers: The MPSim program

Lim, Kian-Tat; Brunett, S.; Iotov, Mihail; McClurg, Richard B.; Vaidehi, Nagarajan; Dasgupta, Sanjoy; Taylor, Stephen; Goddard, William A.

doi:10.1002/(sici)1096-987x(199703)18:4<501::aid-jcc5>3.0.co;2-x

Cited by 82 publications

(69 citation statements)

References 34 publications

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“…The optimized helix bundle is further equilibrated by immersing the protein into a lipid bilayer and performing rigid body molecular dynamics (12,13). The helix bundle surrounded by a lipid bilayer was optimized by using rigid body dynamics.…”

Section: Methodsmentioning

confidence: 99%

Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists

Freddolino

Kalani

Vaidehi

et al. 2004

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

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121

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We report the 3D structure of human ␤2 adrenergic receptor (AR) predicted by using the MembStruk first principles method. To validate this structure, we use the HierDock first principles method to predict the ligand-binding sites for epinephrine and norepinephrine and for eight other ligands, including agonists and antagonists to ␤2 AR and ligands not observed to bind to ␤2 AR. The binding sites agree well with available mutagenesis data, and the calculated relative binding energies correlate reasonably with measured binding affinities. In addition, we find characteristic differences in the predicted binding sites of known agonists and antagonists that allow us to infer the likely activity of other ligands. The predicted ligand-binding properties validate the methods used to predict the 3D structure and function. This validation is a successful step toward applying these procedures to predict the 3D structures and function of the other eight subtypes of ARs, which should enable the development of subtype-specific antagonists and agonists with reduced side effects.T he adrenergic receptors (ARs) are the class of G proteincoupled receptors (GPCR) responsible for mediating the effects of the catecholamines epinephrine and norepinephrine. There are currently nine known human ARs, partitioned into three subclasses: ␣1 (three subtypes located in vascular smooth muscle, the digestive tract, liver, and postsynaptically in the CNS), ␣2 (three subtypes located pre-and postsynaptically in the CNS, and in a wide variety of peripheral sites), and ␤ (three subtypes located primarily in cardiac, vascular, and adipose tissues, respectively).The members of this receptor class mediate a wide variety of physiological responses, including vasodilation and vasoconstriction, heart rate modulation, regulation of lipolysis, and blood clotting. These diverse and important functions make the adrenergic receptors a tempting pharmaceutical target, but attempts to create effective and specific drugs acting on these receptors have been slowed down by the lack of a 3D structure for any GPCR other than the bovine photoreceptor rhodopsin. The focus of this paper is the ␤2AR, which is targeted by agonist therapy in the treatment of asthma. Unfortunately, ␤2 agonists also exhibit crossreactivity with the other ␤ARs, causing side effects such as increased heart rate and blood pressure (1). Three-dimensional models of the ARs would be extremely useful in the design of subtype-specific pharmaceutical compounds. In addition, the ARs have been thoroughly studied experimentally so that there are ample data for validating the structural predictions, which may in turn provide improved understanding for the superfamily of GPCRs.We report here the predicted 3D structure of ␤2AR, which we use to predict detailed binding sites of agonists and antagonists to ␤2AR. This is an excellent case for validation because there is a wealth of experimental data on ligand-binding sites and mutational analysis with which to compare our results (2, 3).We use the MembStruk ...

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Section: Methodsmentioning

confidence: 99%

Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists

Freddolino

Kalani

Vaidehi

et al. 2004

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

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121

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“…All MD simulations and energy minimization were carried out with the MPSim molecular dynamics program. 33 …”

Section: Computational Detailsmentioning

confidence: 99%

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

2005

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Atomistic molecular dynamics simulations are used to study generation 5 polyamidoamine (PAMAM) dendrimers immersed in a bath of water. We interpret the results in terms of three classes of water: buried water well inside of the dendrimer surface, surface water associated with the dendrimer-water interface, and bulk water well outside of the dendrimer. We studied the dynamic and thermodynamic properties of the water at three pH values: high pH with none of the primary or tertiary amines protonated, intermediate pH with only the primary amines protonated, and low pH with all amines protonated. For all pH values we find that both buried and surface water exhibit two relaxation times: a fast relaxation (∼1 ps) corresponding to the libration motion of the water and a slow (∼20 ps) diffusional component related to the escaping of water from one domain to another. In contrast for bulk water the fast relaxation is ∼0.4 ps while the slow relaxation is ∼14 ps. These results are similar to those found in biological systems, where the fast relaxation is found to be ∼1 ps while the slow relaxation ranges from 20 to 1000 ps. We used the 2PT MD method to extract the vibrational (power) spectrum and found substantial differences for the three classes of water. The translational diffusion coefficient for buried water is 11-33% (depending on pH) of the bulk value while the surface water is about 80%. The change in rotational diffusion is quite similar: 21-45% of the bulk value for buried water and 80% for surface water. This shows that translational and rotational dynamics of water are affected by the PAMAM-water interactions as well as due to the confinement in the interior of the dendrimer. We find that the reduction of translational or rotational diffusion is accompanied by a blue shift of the corresponding libration motions (∼10 cm -1 for translation, ∼35 cm -1 for rotation), indicating higher local force constants for these motions. These effects are most pronounced for the lowest pH, probably because of the increased rigidity caused by the internal charges. From the vibrational density of states we also calculate the enthalpies and entropies of the various waters. We find that water molecules are enthalpically favored near the PAMAM dendrimer: energy for surface water is ∼0.1 kcal/mol lower to that in the bulk, and ∼0.5-0.9 kcal/mol lower for buried water. In contrast, we find that both the buried and surface water are entropically unfavored: buried water is 0.9-2.2 kcal/mol lower than the bulk while the surface water is 0.1-0.2 kcal/mol lower. The net result is a thermodynamically unfavored state of the water surrounding the PAMAM dendrimer: 0.4-1.3 kcal/mol higher for buried water and 0.1-0.2 kcal/mol for surface water. This excess free energy of the surface and buried waters is released when the PAMAM dendrimer binds to DNA or metal ions, providing an extra driving force.

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“…͑36͒ is based on minimum energy structures for large clusters. 40 We use it to estimate bulk properties. For smaller clusters, ͑nр147͒ tabulated values were used.…”

Section: ͑35͒mentioning

confidence: 99%

Thermodynamic properties and homogeneous nucleation rates for surface-melted physical clusters

McClurg

Flagan

Goddard

1996

The Journal of Chemical Physics

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We predict the free energy of van der Waals clusters (F n ) in the surface-melted temperature regime. These free energies are used to predict the bulk chemical potential, surface tension, Tolman length, and vapor pressure of noble gas crystals. Together, these estimates allow us to make definitive tests of the capillarity approximation in classical homogeneous nucleation theory. We find that the capillarity approximation underestimates the nucleation rate by thirty orders of magnitude for argon. The best available experiments are consistent with our calculation of nucleation rate as a function of temperature and pressure. We suggest experimental conditions appropriate for determining quantitative nucleation rates which would be invaluable in guiding further development of the theory. To make the predictions of F n , we develop the Shellwise Lattice Search ͑SLS͒ algorithm to identify isomer fragments and the Linear Group Contribution ͑LGC͒ method to estimate the energy of isomers composed of those fragments. Together, SLS/LGC approximates the distribution of isomers which contribute to the configurational partition function ͑for up to 147-atom clusters͒. Estimates of the remaining free energy contributions come from a previous paper in this series.

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Molecular dynamics for very large systems on massively parallel computers: The MPSim program

Cited by 82 publications

References 34 publications

Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists

Predicted 3D structure for the human β2 adrenergic receptor and its binding site for agonists and antagonists

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

Thermodynamic properties and homogeneous nucleation rates for surface-melted physical clusters

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