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At least 163 records · Page 9Linked to original sources
PubMed2004

Computational approach to systems biology: from fraction to integration and beyond.

Systems biology is an approach to understanding the workings of whole biological systems. The various methods used for systems analyses range from experimental to computational. In this paper, we describe basic concepts of systems biology, modeling challenges that arise from the massively parallel interaction among components in biological systems, and what lies beyond integration of modular knowledge.

Animals↗
PubMed2003

Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases.

Modular polyketide synthases (PKSs) are large multi-enzymatic, multi-domain megasynthases, which are involved in the biosynthesis of a class of pharmaceutically important natural products, namely polyketides. These enzymes harbor a set of repetitive active sites termed modules and the domains present in each module dictate the chemical moiety that would add to a growing polyketide chain. This modular logic of biosynthesis has been exploited with reasonable success to produce several novel compounds by genetic manipulation. However, for harnessing their vast potential of combinatorial biosynthesis, it is essential to develop knowledge based in silico approaches for correlating the sequence and domain organization of PKSs to their polyketide products. In this work, we have carried out extensive sequence analysis of experimentally characterized PKS clusters to develop an automated computational protocol for unambiguous identification of various PKS domains in a polypeptide sequence. A structure based approach has been used to identify the putative active site residues of acyltransferase (AT) domains, which control the specificities for various starter and extender units during polyketide biosynthesis. On the basis of the analysis of the active site residues and molecular modelling of substrates in the active site of representative AT domains, we have identified a crucial residue that is likely to play a major role in discriminating between malonate and methylmalonate during selection of extender groups by this domain. Structural modelling has also explained the experimentally observed chiral preference of AT domain in substrate selection. This computational protocol has been used to predict the domain organization and substrate specificity for PKS clusters from various microbial genomes. The results of our analysis as well as the computational tools for prediction of domain organization and substrate specificity have been organized in the form of a searchable computerized database (PKSDB). PKSDB would serve as a valuable tool for identification of polyketide products biosynthesized by uncharacterized PKS clusters. This database can also provide guidelines for rational design of experiments to engineer novel polyketides.

Amino Acid Sequence↗
PubMed2003

A new computational approach for real protein folding prediction.

An effective and fast minimization approach is proposed for the prediction of protein folding, in which the 'relative entropy' is used as a minimization function and the off-lattice model is used. In this approach, we only use the information of distances between the consecutive Calpha atoms along the peptide chain and a generalized form of the contact potential for 20 types of amino acids. Tests of the algorithm are performed on the real proteins. The root mean square deviations of the structures of eight folded target proteins versus the native structures are in a reasonable range. In principle, this method is an improvement on the energy minimization approach.

Algorithms↗
PubMed2002

A computational approach to control in complex cognition.

Cognitive deficits associated with dorsolateral prefrontal cortex (DLPFC) damage are often most apparent in higher cognitive tasks that involve problem solving and managing multiple goals. However, computational models of prefrontal deficits on such tasks are difficult to construct. Problem solving is most naturally modeled with symbolic systems (e.g. production systems), but the effects of lesions are most naturally modeled with subsymbolic systems (neural networks). We show that when we adopt a simple and plausible model of neural computation, there is a natural and explicit mapping from symbolic, goal-driven cognition onto neural computation. We exploit this mapping to construct a neural network model that is capable of solving complex problems in the Tower of London task. The model leads to a specific hypothesis about the role of DLPFC in such tasks, namely, that DLPFC represents internally generated subgoals that modulate competition among posterior representations. When intact, the model accurately simulates the behavior of college students even on the most difficult problems. Furthermore, when the subgoal component is lesioned, it accurately simulates the behavior of prefrontal patients, including the fact that their deficits are most apparent on the most difficult tasks and that they have special difficulty with tasks that require inhibiting a prepotent response.

Cognition↗
PubMed2001

Parallel cortico-basal ganglia mechanisms for acquisition and execution of visuomotor sequences - a computational approach.

Experimental studies have suggested that many brain areas, including the basal ganglia (BG), contribute to procedural learning. Focusing on the basal ganglia-thalamocortical (BG-TC) system, we propose a computational model to explain how different brain areas work together in procedural learning. The BG-TC system is composed of multiple separate loop circuits. According to our model, two separate BG-TC loops learn a visuomotor sequence concurrently but using different coordinates, one visual, and the other motor. The visual loop includes the dorsolateral prefrontal (DLPF) cortex and the anterior part of the BG, while the motor loop includes the supplementary motor area (SMA) and the posterior BG. The concurrent learning in these loops is based on reinforcement signals carried by dopaminergic (DA) neurons that project divergently to the anterior ("visual") and posterior ("motor") parts of the striatum. It is expected, however, that the visual loop learns a sequence faster than the motor loop due to their different coordinates. The difference in learning speed may lead to inconsistent outputs from the visual and motor loops, and this problem is solved by a mechanism called a "coordinator," which adjusts the contribution of the visual and motor loops to a final motor output. The coordinator is assumed to be in the presupplementary motor area (pre-SMA). We hypothesize that the visual and motor loops, with the help of the coordinator, achieve both the quick acquisition of novel sequences and the robust execution of well-learned sequences. A computational model based on the hypothesis is examined in a series of computer simulations, referring to the results of the 2 x 5 task experiments that have been used on both monkeys and humans. We found that the dual mechanism with the coordinator was superior to the single (visual or motor) mechanism. The model replicated the following essential features of the experimental results: (1) the time course of learning, (2) the effect of opposite hand use, (3) the effect of sequence reversal, and (4) the effects of localized brain inactivations. Our model may account for a common feature of procedural learning: A spatial sequence of discrete actions (subserved by the visual loop) is gradually replaced by a robust motor skill (subserved by the motor loop).

Basal Ganglia↗
PubMed1991

A parallel computing approach to genetic sequence comparison: the master-worker paradigm with interworker communication.

We have implemented a parallel version of a dynamic programming biological sequence comparison algorithm to study the potential applicability of using parallel computers for genetic sequence comparisons. Our parallel program is built using C-Linda, a machine-independent parallel programming language, and was tested on both a 10 CPU Sequent Symmetry and a 64 CPU Intel Hypercube. C-Linda implements a shared associative memory model, "tuple space," through which multiple processes can communicate and coordinate control. In our master-worker (MW) parallel implementation, a master process creates several worker processes, extracts a test sequence and multiple library sequences from a database and stores them in tuple space. Each worker reads the test sequence and then repeatedly extracts library strings from tuple space, performs pairwise sequence comparison using a local comparison algorithm to generate a similarity score, and returns the similarity scores to tuple space. The master collects the scores from tuple space and identifies the best match over all library sequences. We also implemented a method of global interworker communication to reduce the total search time by stopping those string comparisons that had no chance of improving on the current best match. Comparisons of the total run time, speedup, and efficiency were made for parallel and sequential versions of a basic MW implementation as well as versions with the global abort threshold.

Algorithms↗
PubMed2002

Development and validation of an integrated computational approach for the study of ionic species in solution by means of effective two-body potentials. The case of Zn2+, Ni2+, and Co2+ in aqueous solutions.

In this paper we have developed an effective computational procedure for the structural and dynamical investigation of ions in aqueous solutions. Quantum mechanical potential energy surfaces for the interaction of a transition metal ion with a water molecule have been calculated taking into account the effect of bulk solvent by the polarizable continuum model (PCM). The effective ion-water interactions have been fitted by suitable analytical potentials, and have been utilized in molecular dynamics (MD) simulations to obtain structural and dynamical properties of the ionic aqueous solutions. This procedure has been successfully applied to the Co2+-H2O open-shell system and, for the first time, Co-oxygen and Co-hydrogen pair potential functions have been determined and employed in MD simulations. The reliability of the whole procedure has been assessed by applying it also to the Zn2+ and Ni2+ aqueous solutions, and the structural and dynamical properties of the three systems have been calculated by means of MD simulations and have been found to be in very good agreement with experimental results. The structural parameters of the first solvation shells issuing from the MD simulations provide an effective complement to extended X-ray absorption fine structure (EXAFS) experiments.

Journal Article↗
PubMed2002

Correlating overrepresented upstream motifs to gene expression: a computational approach to regulatory element discovery in eukaryotes.

BACKGROUND: Gene regulation in eukaryotes is mainly effected through transcription factors binding to rather short recognition motifs generally located upstream of the coding region. We present a novel computational method to identify regulatory elements in the upstream region of eukaryotic genes. The genes are grouped in sets sharing an overrepresented short motif in their upstream sequence. For each set, the average expression level from a microarray experiment is determined: If this level is significantly higher or lower than the average taken over the whole genome, then the overerpresented motif shared by the genes in the set is likely to play a role in their regulation. RESULTS: The method was tested by applying it to the genome of Saccharomyces cerevisiae, using the publicly available results of a DNA microarray experiment, in which expression levels for virtually all the genes were measured during the diauxic shift from fermentation to respiration. Several known motifs were correctly identified, and a new candidate regulatory sequence was determined. CONCLUSIONS: We have described and successfully tested a simple computational method to identify upstream motifs relevant to gene regulation in eukaryotes by studying the statistical correlation between overepresented upstream motifs and gene expression levels.

5' Flanking Region↗
PubMed2006

Toward an integrated computational approach to CW-ESR spectra of free radicals.

Interpretation of structural properties and dynamic behaviour of molecules in solution is of fundamental importance to understand their stability, chemical reactivity and catalytic action. Information can be gained, in principle, by a variety of spectroscopic techniques, magnetic as well as optical. In particular, continuous wave electron spin resonance (CW-ESR) measurements are highly informative. However, the wealth of structural and dynamic information which can be extracted from ESR spectroscopy is, at present, limited by the necessity of employing computationally efficient models, which are increasingly complex as they need to take into account diverse relaxation processes affecting the spectrum. In this paper, we address the basic theoretical tools needed to predict, essentially ab initio, CW-ESR spectra observables according to the stochastic Liouville equation (SLE) approach, combined with quantum mechanical and hybrid methods for the accurate and efficient computation of structural, spectroscopic and magnetic properties of molecular systems. We shall discuss, on one hand, the quantum mechanical calculation of magnetic observables, via density functional theory (DFT), time-dependent DFT (TD-DFT) and application of the polarizable continuum model (PCM) for the description of environmental effects, including anisotropic environments and systems where different regions are characterized by different dielectric constants. One the other hand, the explicit evaluation of dynamical effects will be discussed based on the numerically exact treatment of the SLE in the presence of several relaxation processes, which has been proven to be a challenging task.

Biomechanical Phenomena↗
PubMed1997

Computational approaches for combinatorial library design and molecular diversity analysis.

New approaches for combinatorial library design and molecular diversity analysis have been developed by extending previous work from the fields of quantitative structure-activity relationship, computational chemistry, and chemical information. Recent work has begun to address design efficiency and validation of descriptors for combinatorial library design.

Chemistry, Organic↗