514 research outputs found
The discretised harmonic oscillator: Mathieu functions and a new class of generalised Hermite polynomials
We present a general, asymptotical solution for the discretised harmonic
oscillator. The corresponding Schr\"odinger equation is canonically conjugate
to the Mathieu differential equation, the Schr\"odinger equation of the quantum
pendulum. Thus, in addition to giving an explicit solution for the Hamiltonian
of an isolated Josephon junction or a superconducting single-electron
transistor (SSET), we obtain an asymptotical representation of Mathieu
functions. We solve the discretised harmonic oscillator by transforming the
infinite-dimensional matrix-eigenvalue problem into an infinite set of
algebraic equations which are later shown to be satisfied by the obtained
solution. The proposed ansatz defines a new class of generalised Hermite
polynomials which are explicit functions of the coupling parameter and tend to
ordinary Hermite polynomials in the limit of vanishing coupling constant. The
polynomials become orthogonal as parts of the eigenvectors of a Hermitian
matrix and, consequently, the exponential part of the solution can not be
excluded. We have conjectured the general structure of the solution, both with
respect to the quantum number and the order of the expansion. An explicit proof
is given for the three leading orders of the asymptotical solution and we
sketch a proof for the asymptotical convergence of eigenvectors with respect to
norm. From a more practical point of view, we can estimate the required effort
for improving the known solution and the accuracy of the eigenvectors. The
applied method can be generalised in order to accommodate several variables.Comment: 18 pages, ReVTeX, the final version with rather general expression
Effects of Large-Scale Convection on p-mode Frequencies
We describe an approach for finding the eigenfrequencies of solar acoustic
modes (p modes) in a convective envelope in the WKB limit. This approximation
restricts us to examining the effects of fluid motions which are large compared
to the mode wavelength, but allows us to treat the three-dimensional mode as a
localized ray. The method of adiabatic switching is then used to investigate
the frequency shifts resulting from simple perturbations to a polytropic model
of the convection zone as well as from two basic models of a convective cell.
We find that although solely depth-dependent perturbations can give frequency
shifts which are first order in the strength of the perturbation, models of
convective cells generate downward frequency shifts which are second order in
the perturbation strength. These results may have implications for resolving
the differences between eigenfrequencies derived from solar models and those
found from helioseismic observations.Comment: 27 pages + 6 figures; accepted for publication in Ap
Simple quantitative tests to validate sampling from thermodynamic ensembles
It is often difficult to quantitatively determine if a new molecular
simulation algorithm or software properly implements sampling of the desired
thermodynamic ensemble. We present some simple statistical analysis procedures
to allow sensitive determination of whether a de- sired thermodynamic ensemble
is properly sampled. We demonstrate the utility of these tests for model
systems and for molecular dynamics simulations in a range of situations,
includ- ing constant volume and constant pressure simulations, and describe an
implementation of the tests designed for end users.Comment: 48 pages, 4 figure
Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS
GROMACS is a widely used package for biomolecular simulation, and over the
last two decades it has evolved from small-scale efficiency to advanced
heterogeneous acceleration and multi-level parallelism targeting some of the
largest supercomputers in the world. Here, we describe some of the ways we have
been able to realize this through the use of parallelization on all levels,
combined with a constant focus on absolute performance. Release 4.6 of GROMACS
uses SIMD acceleration on a wide range of architectures, GPU offloading
acceleration, and both OpenMP and MPI parallelism within and between nodes,
respectively. The recent work on acceleration made it necessary to revisit the
fundamental algorithms of molecular simulation, including the concept of
neighborsearching, and we discuss the present and future challenges we see for
exascale simulation - in particular a very fine-grained task parallelism. We
also discuss the software management, code peer review and continuous
integration testing required for a project of this complexity.Comment: EASC 2014 conference proceedin
Computation of Hemagglutinin Free Energy Difference by the Confinement Method
Hemagglutinin (HA) mediates membrane
fusion, a crucial step during
influenza virus cell entry. How many HAs are needed for this process
is still subject to debate. To aid in this discussion, the confinement
free energy method was used to calculate the conformational free energy
difference between the extended intermediate and postfusion state
of HA. Special care was taken to comply with the general guidelines
for free energy calculations, thereby obtaining convergence and demonstrating
reliability of the results. The energy that one HA trimer contributes
to fusion was found to be 34.2 ± 3.4<i>k</i><sub>B</sub><i>T</i>, similar to the known contributions from other
fusion proteins. Although computationally expensive, the technique
used is a promising tool for the further energetic characterization
of fusion protein mechanisms. Knowledge of the energetic contributions
per protein, and of conserved residues that are crucial for fusion,
aids in the development of fusion inhibitors for antiviral drugs
From Heisenberg matrix mechanics to EBK quantization: theory and first applications
Despite the seminal connection between classical multiply-periodic motion and
Heisenberg matrix mechanics and the massive amount of work done on the
associated problem of semiclassical (EBK) quantization of bound states, we show
that there are, nevertheless, a number of previously unexploited aspects of
this relationship that bear on the quantum-classical correspondence. In
particular, we emphasize a quantum variational principle that implies the
classical variational principle for invariant tori. We also expose the more
indirect connection between commutation relations and quantization of action
variables. With the help of several standard models with one or two degrees of
freedom, we then illustrate how the methods of Heisenberg matrix mechanics
described in this paper may be used to obtain quantum solutions with a modest
increase in effort compared to semiclassical calculations. We also describe and
apply a method for obtaining leading quantum corrections to EBK results.
Finally, we suggest several new or modified applications of EBK quantization.Comment: 37 pages including 3 poscript figures, submitted to Phys. Rev.
Noise-Induced Phase Space Transport in Two-Dimensional Hamiltonian Systems
First passage time experiments were used to explore the effects of low
amplitude noise as a source of accelerated phase space diffusion in
two-dimensional Hamiltonian systems, and these effects were then compared with
the effects of periodic driving. The objective was to quantify and understand
the manner in which ``sticky'' chaotic orbits that, in the absence of
perturbations, are confined near regular islands for very long times, can
become ``unstuck'' much more quickly when subjected to even very weak
perturbations. For both noise and periodic driving, the typical escape time
scales logarithmically with the amplitude of the perturbation. For white noise,
the details seem unimportant: Additive and multiplicative noise typically have
very similar effects, and the presence or absence of a friction related to the
noise by a Fluctuation-Dissipation Theorem is also largely irrelevant. Allowing
for colored noise can significantly decrease the efficacy of the perturbation,
but only when the autocorrelation time becomes so large that there is little
power at frequencies comparable to the natural frequencies of the unperturbed
orbit. Similarly, periodic driving is relatively inefficient when the driving
frequency is not comparable to these natural frequencies. This suggests
strongly that noise-induced extrinsic diffusion, like modulational diffusion
associated with periodic driving, is a resonance phenomenon. The logarithmic
dependence of the escape time on amplitude reflects the fact that the time
required for perturbed and unperturbed orbits to diverge a given distance
scales logarithmically in the amplitude of the perturbation.Comment: 15 pages, including 13 Figures and 1 Table, uses Phys. Rev. macro
Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations
Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes problematic, especially for systems larger than small poly peptides. Here, we propose a method of accelerating only the degrees of freedom most pertinent to sampling, thereby reducing the total acceleration added to the system and improving the convergence of calculated ensemble averages, which we term selective aMD. Its application is highlighted in two biomolecular cases. First, the model system alanine dipeptide is simulated with classical MD, all-dihedral aMD, and selective aMD, and these results are compared to the infinite sampling limit as calculated with metadynamics. We show that both forms of aMD enhance the convergence of the underlying free energy landscape by 5-fold relative to classical MD; however, selective aMD can produce improved statistics over all-dihedral aMD due to the improved reweighting. Then we focus on the pharmaceutically relevant case of computing the free energy of the decoupling of oseltamivir in the active site of neuraminidase. Results show that selective aMD greatly reduces the cost of this alchemical free energy transformation, whereas all-dihedral aMD produces unreliable free energy estimates
Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.
Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies
Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir
Free-energy changes are essential physicochemical quantities for understanding most biochemical processes. Yet, the application of accurate thermodynamic-integration (TI) computation to biological and macromolecular systems is limited by finite-sampling artifacts. In this paper, we employ independent-trajectories thermodynamic-integration (IT-TI) computation to estimate improved free-energy changes and their uncertainties for (bio)molecular systems. IT-TI aids sampling statistics of the thermodynamic macrostates for flexible associating partners by ensemble averaging of multiple, independent simulation trajectories. We study peramivir (PVR) inhibition of the H5N1 avian influenza virus neuraminidase flexible receptor (N1). Binding site loops 150 and 119 are highly mobile, as revealed by N1-PVR 20-ns molecular dynamics. Due to such heterogeneous sampling, standard TI binding free-energy estimates span a rather large free-energy range, from a 19% underestimation to a 29% overestimation of the experimental reference value (−62.2 ± 1.8 kJ mol−1). Remarkably, our IT-TI binding free-energy estimate (−61.1 ± 5.4 kJ mol−1) agrees with a 2% relative difference. In addition, IT-TI runs provide a statistics-based free-energy uncertainty for the process of interest. Using ∼800 ns of overall sampling, we investigate N1-PVR binding determinants by IT-TI alchemical modifications of PVR moieties. These results emphasize the dominant electrostatic contribution, particularly through the N1 E277−PVR guanidinium interaction. Future drug development may be also guided by properly tuning ligand flexibility and hydrophobicity. IT-TI will allow estimation of relative free energies for systems of increasing size, with improved reliability by employing large-scale distributed computing
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