1,681 research outputs found
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
Dynamics and calcium association to the N-terminal regulatory domain of human cardiac troponin C: a multiscale computational study.
Troponin C (TnC) is an important regulatory molecule in cardiomyocytes. Calcium binding to site II in TnC initiates a series of molecular events that result in muscle contraction. The most direct change upon Ca(2+) binding is an opening motion of the molecule that exposes a hydrophobic patch on the surface allowing for Troponin I to bind. Molecular dynamics simulations were used to elucidate the dynamics of this crucial protein in three different states: apo, Ca(2+)-bound, and Ca(2+)-TnI-bound. Dynamics between the states are compared, and the Ca(2+)-bound system is investigated for opening motions. On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables. Agreement indicates that the simulations sample the relevant dynamics of the system. Brownian dynamics simulations are used to investigate the calcium association of TnC. We find that calcium binding gives rise to correlative motions involving the EF hand and collective motions conducive of formation of the TnI-binding interface. We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca(2+)
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
Incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam, cefepime, or meropenem
Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish
The treatment of psychiatric disorders presents three major challenges to the research and clinical community: defining a genotype associated with a disorder, characterizing the molecular pathology of each disorder and developing new therapies. This Review addresses how cellular and animal systems can help to meet these challenges, with an emphasis on the role of the zebrafish. Genetic changes account for a large proportion of psychiatric disorders and, as gene variants that predispose to psychiatric disease are beginning to be identified in patients, these are tractable for study in cellular and animal systems. Defining cellular and molecular criteria associated with each disorder will help to uncover causal physiological changes in patients and will lead to more objective diagnostic criteria. These criteria should also define co-morbid pathologies within the nervous system or in other organ systems. The definition of genotypes and of any associated pathophysiology is integral to the development of new therapies. Cell culture-based approaches can address these challenges by identifying cellular pathology and by high-throughput screening of gene variants and potential therapeutics. Whole-animal systems can define the broadest function of disorder-associated gene variants and the organismal impact of candidate medications. Given its evolutionary conservation with humans and its experimental tractability, the zebrafish offers several advantages to psychiatric disorder research. These include assays ranging from molecular to behavioural, and capability for chemical screening. There is optimism that the multiple approaches discussed here will link together effectively to provide new diagnostics and treatments for psychiatric patients
Modeling the electrophoresis of lysozyme. II. Inclusion of ion relaxation
In this work, boundary element methods are used to model the electrophoretic mobility of lysozyme over the pH range 2–6. The model treats the protein as a rigid body of arbitrary shape and charge distribution derived from the crystal structure. Extending earlier studies, the present work treats the equilibrium electrostatic potential at the level of the full Poisson-Boltzmann (PB) equation and accounts for ion relaxation. This is achieved by solving simultaneously the Poisson, ion transport, and Navier-Stokes equations by an iterative boundary element procedure. Treating the equilibrium electrostatics at the level of the full rather than the linear PB equation, but leaving relaxation out, does improve agreement between experimental and simulated mobilities, including ion relaxation improves it even more. The effects of nonlinear electrostatics and ion relaxation are greatest at low pH, where the net charge on lysozyme is greatest. In the absence of relaxation, a linear dependence of mobility and average polyion surface potential, (lambda zero)s, is observed, and the mobility is well described by the equation [formula: see text] where epsilon 0 is the dielectric constant of the solvent, and eta is the solvent viscosity. This breaks down, however, when ion relaxation is included and the mobility is less than predicted by the above equation. Whether or not ion relaxation is included, the mobility is found to be fairly insensitive to the charge distribution within the lysozyme model or the internal dielectric constant
Substrate concentration dependence of the diffusion-controlled steady-state rate constant
The Smoluchowski approach to diffusion-controlled reactions is generalized to
interacting substrate particles by including the osmotic pressure and
hydrodynamic interactions of the nonideal particles in the Smoluchoswki
equation within a local-density approximation. By solving the strictly
linearized equation for the time-independent case with absorbing boundary
conditions, we present an analytic expression for the diffusion-limited
steady-state rate constant for small substrate concentrations in terms of an
effective second virial coefficient B_2*. Comparisons to Brownian dynamics
simulations excluding HI show excellent agreement up to bulk number densities
of B_2* rho_0 < 0.4 for hard sphere and repulsive Yukawa-like interactions
between the substrates. Our study provides an alternative way to determine the
second virial coefficient of interacting macromolecules experimentally by
measuring their steady-state rate constant in diffusion-controlled reactions at
low densities.Comment: 7 pages, 3 figure
Contribution of Unresolved Point Sources to the Diffuse X-ray Background below 1 keV
We present here the analysis of X-rays point sources detected in several
observations available in the XMM-Newton public archive. We focused, in
particular, on energies below 1 keV, which are of particular relevance to the
understanding of the Diffuse X-ray Background. The average field of all the
exposures is 0.09 deg^-2. We reached an average flux sensitivity of 5.8x10^-16
erg s^-1 cm^-2 in the soft band (0.5-2.0 keV) and 2.5x10^-16 erg s^-1 cm^-2 in
the very soft band (0.4-0.6 keV). In this paper we discuss the logN-logS
results, the contribution to the integrated X-ray sky flux, and the properties
of the cumulative spectrum from all sources. In particular, we found an excess
flux at around 0.5 keV in the composite spectrum of faint sources. The excess
seems to be a general property of all the fields observed suggesting an
additional class of weak sources is contributing to the X-ray emission at these
energies. Combining our results with previous investigations we have also
quantified the contribution of the individual components of the diffuse X-ray
Background in the 3/4 keV band.Comment: Accepted for publication in ApJ; 27 pages, 8 figure
Vibration Isolation Design for the Micro-X Rocket Payload
Micro-X is a NASA-funded, sounding rocket-borne X-ray imaging spectrometer
that will allow high precision measurements of velocity structure, ionization
state and elemental composition of extended astrophysical systems. One of the
biggest challenges in payload design is to maintain the temperature of the
detectors during launch. There are several vibration damping stages to prevent
energy transmission from the rocket skin to the detector stage, which causes
heating during launch. Each stage should be more rigid than the outer stages to
achieve vibrational isolation. We describe a major design effort to tune the
resonance frequencies of these vibration isolation stages to reduce heating
problems prior to the projected launch in the summer of 2014.Comment: 6 pages, 7 figures, LTD15 Conference Proceeding
- …