A general user interface for prediction servers of proteins' post-translational modification sites

Post-translational modifications (PTMs) of proteins play essential roles in governing the functions and dynamics of proteins and are implicated in many cellular processes. Several types of PTMs have been investigated through computational approaches, including phosphorylation, sumoylation, palmitoylation, and lysine and arginine methylation, among others. Because the large diversity in the user interfaces (UIs) of different prediction servers for PTMs could possibly hinder experimental biologists in using these servers, we propose to develop a protocol for a unified UI for PTM prediction servers, based on our own work and that of other groups on PTM site prediction. By following this protocol, tool developers can provide a uniform UI regardless of the PTM types and the underlying computational algorithms. With such uniformity in the UI, experimental biologists would be able to use any PTM prediction server compliant with this protocol once they had learned to use one of them. It takes a typical PTM prediction server compliant with this unified UI several minutes to calculate the prediction results for a protein 1,000 amino acids in length.     

Software tools for motif and pattern scanning: program descriptions including a universal sequence reading algorithm

Two programs, MOTIF and PATTERN, that scan sequences for matchesto user-defined motifs and patterns of motifs based on identityand set membership are described. The programs use a simpleand logical notation to define motifs, and may be used eitherinteractively or by using command line parameters (suitablefor batch processing). The two programs described also incorporatea simple, yet reliable, algorithm that automatically detectsin which of six possible formats the sequence entry is written. Received on February 28, 1989; accepted on April 4, 1989     

Molecular Dynamics Simulation on a Parallel Computer

For the purpose of molecular dynamics simulations of large biopolymers we have built a parallel computer with a systolic loop architecture, based on Transputers as computational units, and have programmed it in occam II. The computational nodes of the computer are linked together in a systolic ring. The program based on this topology for large biopolymers increases its computational throughput nearly linearly with the number of computational nodes. The program developed is closely related to the simulation programs CHARMM and XPLOR, the input files required (force field, protein structure file, coordinates) and output files generated (sets of atomic coordinates representing dynamic trajectories and energies) are compatible with the corresponding files of these programs. Benchmark results of simulations of biopolymers comprising 66, 568, 3 634, 5 797 and 12 637 atoms are compared with XPLOR simulations on conventional computers (Cray, Convex, Vax). These results demonstrate that the software and hardware developed provide extremely cost effective biopolymer simulations. We present also a simulation (equilibrium of X-ray structure) of the complete photosynthetic reaction center of Rhodopseudomonas viridis (12 637 atoms). The simulation accounts for the Coulomb forces exactly, i.e. no cut-off had been assumed.     

Adaptive dynamic programming as a theory of sensorimotor control

Many characteristics of sensorimotor control can be explained by models based on optimization and optimal control theories. However, most of the previous models assume that the central nervous system has access to the precise knowledge of the sensorimotor system and its interacting environment. This viewpoint is difficult to be justified theoretically and has not been convincingly validated by experiments. To address this problem, this paper presents a new computational mechanism for sensorimotor control from a perspective of adaptive dynamic programming (ADP), which shares some features of reinforcement learning. The ADP-based model for sensorimotor control suggests that a command signal for the human movement is derived directly from the real-time sensory data, without the need to identify the system dynamics. An iterative learning scheme based on the proposed ADP theory is developed, along with rigorous convergence analysis. Interestingly, the computational model as advocated here is able to reproduce the motor learning behavior observed in experiments where a divergent force field or velocity-dependent force field was present. In addition, this modeling strategy provides a clear way to perform stability analysis of the overall system. Hence, we conjecture that human sensorimotor systems use an ADP-type mechanism to control movements and to achieve successful adaptation to uncertainties present in the environment.     

Rigid-body modeling of knee cartilage and meniscus using experimental pressure-strain curves

Rigid-body knee models have gained popularity thanks to computational speed and ease of setup compared to finite element models—showing exciting potential for clinical patient-specific models in the future. However, Rigid-body studies in general have encountered difficulty in modeling cartilage and especially meniscus material properties, often relying on computationally costly optimization techniques. This paper presents two new methods to alleviate the difficulty—one to define model contact pressure and one to define meniscus internal forces—and is the first to our knowledge to use experimental pressure-strain curves from the literature to simulate cartilage and meniscus behavior in a rigid body model. This paper describes the methodology to derive the proof of concept model and preliminary results from a gait simulation based on ISO 14243-1.     

A communication-efficient linear system solver for large eddy simulation of jet engine noise

High-fidelity computational fluid dynamics (CFD) tools, such as the large eddy simulation technique, have become feasible in aiding the field of computational aeroacoustics (CAA) to compute noise on petascale computing platforms. CAA poses significant challenges for researchers because the computational schemes used in the CFD tools should have high accuracy, good spectral resolution, and low dispersion and diffusion errors. A high-order compact finite difference scheme, which is implicit in space, can be used for such simulations because it fulfills the requirements for CAA. Usually, this method is parallelized using a transposition scheme; however, that approach has a high communication overhead. In this paper, we discuss the use of a parallel tridiagonal linear system solver based on the truncated SPIKE algorithm for reducing the communication overhead in our large eddy simulations. We present theoretical performance analysis and report experimental results collected on two parallel computing platforms.     

Oxadiazole scaffolds in anti-tuberculosis drug discovery

With the increasing number of cases of latent and drug resistant tuberculosis, there is an urgent need to develop new, potent molecules capable of combating this deadly disease. Molecules containing oxadiazoles are one such class that could be considered to fulfil this need. Oxadiazole regioisomers have been explored in drug discovery programs for their ability to act as effective linkers and also as pharmacophoric features. Oxadiazoles can act as bioisosteric replacements for the hydrazide moiety which can be found in first line anti-TB drugs, and some have been also reported to interact with newer anti-TB targets. In this context, the present review describes the potential of oxadiazoles as antituberculosis agents.     

DMLE+: Bayesian linkage disequilibrium gene mapping

SUMMARY: The program DMLE+ allows Bayesian inference of the location of a gene carrying a mutation influencing a discrete trait (such as a disease) and/or other parameters of interest (such as mutation age) based on the observed linkage disequilibrium at multiple genetic markers. DMLE+ uses either individual marker genotypes, or haplotypes, integrates over uncertain population allele frequencies, and can incorporate prior information about gene location from an annotated human genome sequence. AVAILABILITY: DMLE+ is available in both Windows GUI and portable UNIX command line versions at http://dmle.org.     

Stiefel-manifold learning by improved rigid-body theory applied to ICA

In previous contributions we presented a new class of algorithms for orthonormal learning of a linear neural network with p inputs and m outputs, based on the equations describing the dynamics of a massive rigid frame in a submanifold of R(p). While exhibiting interesting features, such as intrinsic numerical stability, strongly binding to the orthonormal submanifolds, and good controllability of the learning dynamics, tested on principal/independent component analysis, the proposed algorithms were not completely satisfactory from a computational-complexity point of view. The main drawback was the need to repeatedly evaluate a matrix exponential map. With the aim to lessen the computational efforts pertaining to these algorithms, we propose here an improvement based on the closed-form Rodriguez formula for the exponential map. Such formula is available in the p = 3 and m = 3 case, which is discussed with details here. In particular, experimental results on independent component analysis (ICA), carried out with both synthetic and real-world data, help confirming the computational gain due to the proposed improvement.     

Estimation of the diffusion rate and crossing probability for biased edge movement between two different types of habitat

One of the fundamental goals of ecology is to examine how dispersal affects the distribution and dynamics of insects across natural landscapes. These landscapes are frequently divided into patches of habitat embedded in a matrix of several non-habitat regions, and dispersal behavior could vary within each landscape element as well as the edges between elements. Reaction–diffusion models are a common way of modeling dispersal and species interactions in such landscapes, but to apply these models we also need methods of estimating the diffusion rate and any edge behavior parameters. In this paper, we present a method of estimating the diffusion rate using the mean occupancy time for a circular region. We also use mean occupancy time to estimate a parameter (the crossing probability) that governs one type of edge behavior often used in these models, a biased random walk. These new methods have some advantages over other methods of estimating these parameters, including reduced computational cost and ease of use in the field. They also provide a method of estimating the diffusion rate for a particular location in space, compared to existing methods that represent averages over large areas. We further examine the statistical properties of the new method through simulation, and discuss how mean occupancy time could be estimated in field experiments.     

气候变化和土地利用变化驱动下的生物多样性系统分析新框架

尽管目前已有大量关于生物多样性评估的研究,但同时考虑生物多样性多维评估、多驱动因素对生物多样性变化的影响评估及生物多样性变化中长期动态模拟预测等研究仍相对缺乏,这会引起对生物多样性不同维度变化水平的片面理解,导致生物多样性保护工程管理决策失误。基于此,综述现有生物多样性评估维度、驱动因素及历史评估的研究进展,并基于现有研究存在的局限性提出生物多样性多维评估方法与人地耦合系统下生物多样性模拟模型构建思路,基于此提出气候变化和土地利用变化驱动下的生物多样性系统分析新框架。该框架包括:①生物多样性"潜力-贡献-重要性"多维评估理论与方法构建;②人地耦合系统下生物多样性模拟模型构建;③人地耦合系统下生物多样性预测及生物多样性保护工程效果仿真与管理。该框架可为生物多样性保护工程管理及可持续开展提供科学建议。     

Quantifying the hydrodynamic stress for bioprocesses

Hydrodynamic stress is an influential physical parameter for various bioprocesses, affecting the performance and viability of the living organisms. However, different approaches are in use in various computational and experimental studies to calculate this parameter (including its normal and shear subcomponents) from velocity fields without a consensus on which one is the most representative of its effect on living cells. In this letter, we investigate these different methods with clear definitions and provide our suggested approach which relies on the principal stress values providing a maximal distinction between the shear and normal components. Furthermore, a numerical comparison is presented using the computational fluid dynamics simulation of a stirred and sparged bioreactor. It is demonstrated that for this specific bioreactor, some of these methods exhibit quite similar patterns throughout the bioreactor—therefore can be considered equivalent—whereas some of them differ significantly.     

Molecular dynamics simulations of the lipid bilayer edge

Phospholipid bilayers have been intensively studied by molecular dynamics (MD) simulation in recent years. The properties of bilayer edges are important in determining the structure and stability of pores formed in vesicles and biomembranes. In this work, we use molecular dynamics simulation to investigate the structure, dynamics, and line tension of the edges of bilayer ribbons composed of pure dimyristoylphosphatidylcholine (DMPC) or palmitoyl-oleoylphosphatidylethanolamine (POPE). As expected, we observe a significant reorganization of lipids at and near the edges. The treatment of electrostatic effects is shown to have a qualitative impact on the structure and stability of the edge, and significant differences are observed in the dynamics and structure of edges formed by DMPC and palmitoyl-oleoylphosphatidylethanolamine. From the pressure anisotropy in the simulation box, we calculate a line tension of approximately 10-30 pN for the DMPC edge, in qualitative agreement with experimental estimates for similar lipids.     

A hybrid systems framework for cellular processes

With the availability of technologies that allow us to obtain stimulus-response time series data for modeling and system identification, there is going to be an increasing need for conceptual frameworks in which to formulate and test hypotheses about intra- and inter-cellular dynamics, in general and not just dependent on a particular cell line, cell type, organism, or technology. While the semantics can be quite different, biologists and systems scientists use in many cases a similar language (notion of feedback, regulation, etc.). A more abstract system-theoretic framework for signals, systems, and control could provide the biologist with an interface between the domains. Apart from recent examples to identify functional elements and describing them in engineering terms, there have been various more abstract developments to describe dynamics at the cell level in the past. This includes Rosen's (M,R)-systems. This paper presents an abstract and general compact mathematical framework of intracellular dynamics, regulation and regime switching inspired by (M,R)-theory and based on hybrid automata.     

Simulation tools for biochemical networks: evaluation of performance and usability

MOTIVATION: Simulation of dynamic biochemical systems is receiving considerable attention due to increasing availability of experimental data of complex cellular functions. Numerous simulation tools have been developed for numerical simulation of the behavior of a system described in mathematical form. However, there exist only a few evaluation studies of these tools. Knowledge of the properties and capabilities of the simulation tools would help bioscientists in building models based on experimental data. RESULTS: We examine selected simulation tools that are intended for the simulation of biochemical systems. We choose four of them for more detailed study and perform time series simulations using a specific pathway describing the concentration of the active form of protein kinase C. We conclude that the simulation results are convergent between the chosen simulation tools. However, the tools differ in their usability, support for data transfer to other programs and support for automatic parameter estimation. From the experimentalists' point of view, all these are properties that need to be emphasized in the future.     

Water dynamics clue to key residues in protein folding

A computational method independent of experimental protein structure information is proposed to recognize key residues in protein folding, from the study of hydration water dynamics. Based on all-atom molecular dynamics simulation, two key residues are recognized with distinct water dynamical behavior in a folding process of the Trp-cage protein. The identified key residues are shown to play an essential role in both 3D structure and hydrophobic-induced collapse. With observations on hydration water dynamics around key residues, a dynamical pathway of folding can be interpreted.