2,213 research outputs found
Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach.
To address the problem of specificity in G-protein coupled receptor (GPCR) drug discovery, there has been tremendous recent interest in allosteric drugs that bind at sites topographically distinct from the orthosteric site. Unfortunately, structure-based drug design of allosteric GPCR ligands has been frustrated by the paucity of structural data for allosteric binding sites, making a strong case for predictive computational methods. In this work, we map the surfaces of the beta1 (beta1AR) and beta2 (beta2AR) adrenergic receptor structures to detect a series of five potentially druggable allosteric sites. We employ the FTMAP algorithm to identify 'hot spots' with affinity for a variety of organic probe molecules corresponding to drug fragments. Our work is distinguished by an ensemble-based approach, whereby we map diverse receptor conformations taken from molecular dynamics (MD) simulations totaling approximately 0.5 micros. Our results reveal distinct pockets formed at both solvent-exposed and lipid-exposed cavities, which we interpret in light of experimental data and which may constitute novel targets for GPCR drug discovery. This mapping data can now serve to drive a combination of fragment-based and virtual screening approaches for the discovery of small molecules that bind at these sites and which may offer highly selective therapies
The structure of galactic HI in directions of low total column density
A detailed 21 cm study of areas of that have the smallest known amount of HI in the northern sky was performed. These observations were corrected for stray radiation. The region of main interest, around alpha = 10(h)45(m), delta = 57 deg 20', has a minimium N(HI) of 4.5 x 10 to the 19th power/sq cm. Spectra taken at 21' resolution over a field 4 x 3 deg in this direction show up to four HI line components. Two, near 0 and -50 km/s, are ubiquitous. There is also a narrow component at -10 km/s attributable to a diffuse cloud covering half of the field, and scattered patches of HI at v -100 km/s. the low and intermediate velocity components have a broad line width and are so smoothly distributed across the region that it is unlikely that they contain significant unresolved angular structure. Eight other low column density directions were also observed. Their spectra typically have several components, but the total column density is always 7 x 10 to the 19th power/sq cm and changes smoothly along a 2 deg strip. Half of the directions show narrow lines arising from weak diffuse HI clouds that contain 0.5 to 3.0 x 10 to the 19th power/sq cm
Small scale H I structure and the soft X-ray background
The observed anticorrelation between diffuse soft X-ray flux and H I column density has been explained as absorption of soft X-rays produced in a hot galactic halo, assuming that the neutral interstellar material is sufficiently clumped to reduce the soft X-ray absorption cross section by a factor of two to three. A 21 cm emission line study of H I column density variations at intermediate and high galactic latitudes to 10' spatial resolution has been done. The results confirm conclusions from preliminary work at coarser resolution, and in combination with other data appear to rule out the hypothesis that clumping of neutral interstellar matter on any angular scale significantly reduces X-ray absorption cross sections in the 0.13 - 0.28 keV energy range. It is concluded therefore that the observed anticorrelation is not primarily a consequence of absorption of soft X-rays produced in a hot galactic halo
Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors.
Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand
Coupling hydrophobic, dispersion, and electrostatic contributions in continuum solvent models
Recent studies of the hydration of micro- and nanoscale solutes have
demonstrated a strong {\it coupling} between hydrophobic, dispersion and
electrostatic contributions, a fact not accounted for in current implicit
solvent models. We present a theoretical formalism which accounts for coupling
by minimizing the Gibbs free energy with respect to a solvent volume exclusion
function. The solvent accessible surface is output of our theory. Our method is
illustrated with the hydration of alkane-assembled solutes on different length
scales, and captures the strong sensitivity to the particular form of the
solute-solvent interactions in agreement with recent computer simulations.Comment: 11 pages, 2 figure
Thermal detectors as X-ray spectrometers
Sensitive thermal detectors should be useful for measuring very small energy pulses, such as those produced by the absorption of X-ray photons. The measurement uncertainty can be very small, making the technique promising for high resolution nondispersive X-ray spectroscopy. The limits to the energy resolution of such thermal detectors are derived and used to find the resolution to be expected for a detector suitable for X-ray spectroscopy in the 100 eV to 10,000 eV range. If there is no noise in the thermalization of the X-ray, resolution better than 1 eV full width at half maximum is possible for detectors operating at 0.1 K. Energy loss in the conversion of the photon energy to heat is a potential problem. The loss mechanisms may include emission of photons or electrons, or the trapping of energy in long lived metastable states. Fluctuations in the phonon spectrum could also limit the resolution if phonon relaxation times are very long. Conceptual solutions are given for each of these possible problems
Simple estimation of absolute free energies for biomolecules
One reason that free energy difference calculations are notoriously difficult
in molecular systems is due to insufficient conformational overlap, or
similarity, between the two states or systems of interest. The degree of
overlap is irrelevant, however, if the absolute free energy of each state can
be computed. We present a method for calculating the absolute free energy that
employs a simple construction of an exactly computable reference system which
possesses high overlap with the state of interest. The approach requires only a
physical ensemble of conformations generated via simulation, and an auxiliary
calculation of approximately equal central-processing-unit (CPU) cost.
Moreover, the calculations can converge to the correct free energy value even
when the physical ensemble is incomplete or improperly distributed. As a "proof
of principle," we use the approach to correctly predict free energies for test
systems where the absolute values can be calculated exactly, and also to
predict the conformational equilibrium for leucine dipeptide in implicit
solvent.Comment: To appear in J. Chem. Phys., 10 pages, 6 figure
Constraints on the Interactions between Dark Matter and Baryons from the X-ray Quantum Calorimetry Experiment
Although the rocket-based X-ray Quantum Calorimetry (XQC) experiment was
designed for X-ray spectroscopy, the minimal shielding of its calorimeters, its
low atmospheric overburden, and its low-threshold detectors make it among the
most sensitive instruments for detecting or constraining strong interactions
between dark matter particles and baryons. We use Monte Carlo simulations to
obtain the precise limits the XQC experiment places on spin-independent
interactions between dark matter and baryons, improving upon earlier analytical
estimates. We find that the XQC experiment rules out a wide range of
nucleon-scattering cross sections centered around one barn for dark matter
particles with masses between 0.01 and 10^5 GeV. Our analysis also provides new
constraints on cases where only a fraction of the dark matter strongly
interacts with baryons.Comment: 15 pages, 9 figures. Extended discussion of methodology, to appear in
PR
Hierarchical Orthogonal Matrix Generation and Matrix-Vector Multiplications in Rigid Body Simulations
In this paper, we apply the hierarchical modeling technique and study some
numerical linear algebra problems arising from the Brownian dynamics
simulations of biomolecular systems where molecules are modeled as ensembles of
rigid bodies. Given a rigid body consisting of beads, the
transformation matrix that maps the force on each bead to 's
translational and rotational forces (a vector), and the row
space of , we show how to explicitly construct the matrix
consisting of orthonormal basis vectors of
(orthogonal complement of ) using only operations
and storage. For applications where only the matrix-vector multiplications
and are needed, we introduce
asymptotically optimal hierarchical algorithms without
explicitly forming . Preliminary numerical results are presented to
demonstrate the performance and accuracy of the numerical algorithms
Method to Predict Crowding Effects by Postprocessing Molecular Dynamics Trajectories: Application to the Flap Dynamics of HIV-1 Protease.
The internal dynamics of proteins inside of cells may be affected by the crowded intracellular environments. Here, we test a novel approach to simulations of crowding, in which simulations in the absence of crowders are postprocessed to predict crowding effects, against the direct approach of simulations in the presence of crowders. The effects of crowding on the flap dynamics of HIV-1 protease predicted by the postprocessing approach are found to agree well with those calculated by the direct approach. The postprocessing approach presents distinct advantages over the direct approach in terms of accuracy and speed and is expected to have broad impact on atomistic simulations of macromolecular crowding
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