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PubMed2004

Predicting GPCR-G-protein coupling using hidden Markov models.

MOTIVATION: Determining the coupling specificity of G-protein coupled receptors (GPCRs) is important for understanding the biology of this class of pharmacologically important proteins. Currently available in silico methods for predicting GPCR-G-protein coupling specificity have high error rate. METHOD: We introduce a new approach for creating hidden Markov models (HMMs) based on a first guess about the importance of various residues. We call these knowledge restricted HMMs to emphasize the fact that the state space of the HMM is restricted by the application of a priori knowledge. Specifically, we use only those amino acid residues of GPCRs which are likely to interact with G-proteins, namely those that are predicted to be in the intra-cellular loops. Furthermore, we concatenate these predicted loops into one sequence rather than considering them as four disparate units. This reduces the HMM state space by drastically decreasing the sequence length. RESULTS: Our knowledge restricted HMM based method to predict GPCR-G-protein coupling specificity has an error rate of <1%, when applied to a test set of GPCRs with known G-protein coupling specificity. AVAILABILITY: Academic users can get the data set mentioned herein and HMMs from the authors.

Binding Sites↗
PubMed2004

Prediction of class I T-cell epitopes: evidence of presence of immunological hot spots inside antigens.

MOTIVATION: Processing and presentation of major histocompatibility complex class I antigens to cytotoxic T-lymphocytes is crucial for immune surveillance against intracellular bacteria, parasites, viruses and tumors. Identification of antigenic regions on pathogen proteins will play a pivotal role in designer vaccine immunotherapy. We have developed a system that not only identifies high binding T-cell antigenic epitopes, but also class I T-cell antigenic clusters termed immunological hot spots. METHODS: MULTIPRED, a computational system for promiscuous prediction of HLA class I binders, uses artificial neural networks (ANN) and hidden Markov models (HMM) as predictive engines. The models were rigorously trained, tested and validated using experimentally identified HLA class I T-cell epitopes from human melanoma related proteins and human papillomavirus proteins E6 and E7. We have developed a scoring scheme for identification of immunological hot spots for HLA class I molecules, which is the sum of the highest four predictions within a window of 30 amino acids. RESULTS: Our predictions against experimental data from four melanoma-related proteins showed that MULTIPRED ANN and HMM models could predict T-cell epitopes with high accuracy. The analysis of proteins E6 and E7 showed that ANN models appear to be more accurate for prediction of HLA-A3 hot spots and HMM models for HLA-A2 predictions. For illustration of its utility we applied MULTIPRED for prediction of promiscuous T-cell epitopes in all four SARS coronavirus structural proteins. MULTIPRED predicted HLA-A2 and HLA-A3 hot spots in each of these proteins.

Algorithms↗
PubMed2005

Discriminating between rate heterogeneity and interspecific recombination in DNA sequence alignments with phylogenetic factorial hidden Markov models.

MOTIVATION: A recently proposed method for detecting recombination in DNA sequence alignments is based on the combination of hidden Markov models (HMMs) with phylogenetic trees. Although this method was found to detect breakpoints of recombinant regions more accurately than most existing techniques, it inherently fails to distinguish between recombination and rate variation. In the present paper, we propose to marry the phylogenetic tree to a factorial HMM (FHMM). The states of the first hidden chain represent tree topologies, whereas the states of the second independent hidden chain represent different global scaling factors of the branch lengths. Inference is done in terms of a hierarchical Bayesian model, where parameters and hidden states are sampled from the posterior distribution with Gibbs sampling. RESULTS: We have tested the proposed model on various synthetic and real-world DNA sequence alignments. The simulation results suggest that as opposed to the standard phylogenetic HMM, the phylogenetic FHMM clearly distinguishes between recombination and rate heterogeneity and thereby avoids the prediction of spurious recombinant regions. AVAILABILITY: The proposed method has been implemented in a MATLAB package that extends Kevin Murphy's HMM toolbox. Software and data used in our study are available from http://www.bioss.sari.ac.uk/~dirk/Supplements

Algorithms↗
PubMed2005

Calibrating E-values for hidden Markov models using reverse-sequence null models.

MOTIVATION: Hidden Markov models (HMMs) calculate the probability that a sequence was generated by a given model. Log-odds scoring provides a context for evaluating this probability, by considering it in relation to a null hypothesis. We have found that using a reverse-sequence null model effectively removes biases owing to sequence length and composition and reduces the number of false positives in a database search. Any scoring system is an arbitrary measure of the quality of database matches. Significance estimates of scores are essential, because they eliminate model- and method-dependent scaling factors, and because they quantify the importance of each match. Accurate computation of the significance of reverse-sequence null model scores presents a problem, because the scores do not fit the extreme-value (Gumbel) distribution commonly used to estimate HMM scores' significance. RESULTS: To get a better estimate of the significance of reverse-sequence null model scores, we derive a theoretical distribution based on the assumption of a Gumbel distribution for raw HMM scores and compare estimates based on this and other distribution families. We derive estimation methods for the parameters of the distributions based on maximum likelihood and on moment matching (least-squares fit for Student's t-distribution). We evaluate the modeled distributions of scores, based on how well they fit the tail of the observed distribution for data not used in the fitting and on the effects of the improved E-values on our HMM-based fold-recognition methods. The theoretical distribution provides some improvement in fitting the tail and in providing fewer false positives in the fold-recognition test. An ad hoc distribution based on assuming a stretched exponential tail does an even better job. The use of Student's t to model the distribution fits well in the middle of the distribution, but provides too heavy a tail. The moment-matching methods fit the tails better than maximum-likelihood methods. AVAILABILITY: Information on obtaining the SAM program suite (free for academic use), as well as a server interface, is available at http://www.soe.ucsc.edu/research/compbio/sam.html and the open-source random sequence generator with varying compositional biases is available at http://www.soe.ucsc.edu/research/compbio/gen_sequence

Algorithms↗
PubMed1984

Classification and characterization of cardiac isomyosins.

The structural properties of cardiac isomyosins from several species were compared using native gel electrophoresis, analysis of proteolytic digests, analysis of monoclonal antibody reactivity to specific proteolytic fragments on electroblots and S1 nuclease mapping with cDNA probes. The structure of specific regions of the myosin molecule was analyzed by reacting monoclonal antibodies with chymotryptic peptides of myosin separated by two-dimensional electrophoresis. The pattern of fragments reactive with antibody CCM-52 (epitope in LMM) was identical in all types of V3 isomyosin examined, and different in each type of V1 isomyosin. Peptides reactive with RCM-79 (epitope in HMM) were different from those reactive with CCM-52 and were also significantly different in each type of myosin examined. Thus, HC-alpha is structurally similar in the LMM portion of the molecule in all animals examined, while in the HMM region there are significant structural differences. HC-alpha differs from HC-beta, with structural differences in both LMM and HMM. We have also shown that atrial myosin HC and ventricular HC-alpha in the rabbit are indistinguishable both by RIA and peptide mapping analysis. The same conclusion was derived after analysis of the myosin HC mRNA expressed in rabbit atria and ventricles. Using cDNA probes specific for the alpha and beta myosin HC mRNA, we could not distinguish between the atrial myosin mRNA and ventricular HC alpha (V1 isomyosin) mRNA by S1 nuclease mapping experiments. Classification of different cardiac myosins is largely based on their mobility on native gel electrophoresis, immunological cross-reactivity, and ATPase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Interaction of myosin.ADP.fluorometal complexes with fluorescent probes and direct observation using quick-freeze deep-etch electron microscopy.

Myosin forms stable ternary complexes with ADP and phosphate analogues of fluorometals that mimic different ATPase reaction intermediates corresponding to each step of the cross-bridge cycle. In the present study, we monitored the formation of ternary complexes of myosin.ADP.fluorometal using the fluorescence probe prodan. It has been reported that the fluorescence changes of the probe reflect the formation of intermediates in the ATPase reaction [Hiratsuka (1998) Biochemistry 37, 7167-7176]. Prodan bound to skeletal muscle heavy-mero-myosin (HMM).ADP.fluorometal, with each complex showing different fluorescence spectra. Prodan bound to the HMM.ADP.BeFn complex showed a slightly smaller red-shift than other complexes in the presence of ATP, suggesting a difference in the localized conformation or a difference in the population of BeFn species of global shape. We also examined directly the global structure of the HMM.ADP.fluorometal complexes using quick-freeze deep-etch replica electron microscopy. The HMM heads in the absence of nucleotides were mostly straight and elongated. In contrast, the HMM heads of ternary complexes showed sharply kinked or rounded configurations as seen in the presence of ATP. This is the first report of the direct observation of myosin-ADP-fluorometal ternary complexes, and the results suggest that these complexes indeed mimic the shape of the myosin head during ATP hydrolysis.

Adenosine Diphosphate↗
PubMedDate not supplied

Hereditary multiple malformation in Japanese quail: a possible powerful animal model for morphogenetic studies.

Hereditary multiple malformation (HMM), a new mutation of Japanese quail (Coturnix japonica), is controlled by an autosomal recessive gene. The proposed gene symbol for the mutant gene is hmm. The majority of the homozygotes die at the sixth day of incubation, and the remainder die at various stages by 15 days of incubation. The homozygotes surviving to the late embryonic stage have greatly shortened lower and upper beaks that are set apart and show an early embryo-like body shape, with feather buds but no plumules. Furthermore, they show syndactylous polydactyly in both fore and hind limbs. In the abdomen of the homozygote, a part of the ventriculus, liver, and small intestine protrudes out of the umbilicus region. In the skeleton of the late HMM embryos, ossification is generally delayed and morphogenetic abnormalities are observed all over the body. This mutant seems to become a powerful animal model in the research fields for morphogenesis.

Abnormalities, Multiple↗
PubMed1992

Muscle actin cleaved by proteinase K: its polymerization and in vitro motility.

Skeletal muscle actin was lightly digested by proteinase K, which cleaved the peptide bond between Met-47 and Gly-48, producing a C-terminal 35 kDa fragment. Proteinase K-cleaved actin (proK-actin) did not polymerize into F-actin upon addition of salt. In the presence of phalloidin, however, it polymerized slowly into F-actin (proK-F-actin), indicating that the cleaved actin did not dissociate into the individual cleaved fragments but retained the global structure of actin. Electron microscopy showed that proK-F-actin had the typical double-stranded structure of a normal actin filament and formed the arrowhead structure when decorated with HMM. Heavy meromyosin ATPase was weakly activated by proK-F-actin: Vmax = 0.24 s-1, and Kapp = 2.8 microM, while Vmax = 7.6 s-1, and Kapp = 13 microM by F-actin. Correspondingly, in vitro this proK-F-actin slid very slowly on HMM attached to a glass surface at an average velocity of 0.47 microns/s, or 1/12 of that of intact F-actin. The fraction of sliding filaments was less than 50%. Assuming that the nonmotile filaments attached to HMM were not involved in ATPase activation, the sliding velocity correlated with the ATPase activity activated by proK-F-actin.

Actins↗
PubMed1976

Reaction intermediates of H-meromyosin-ATPase and ultraviolet difference spectrum of H-meromyosin induced by ATP.

UV Difference spectra of H-meromyosin (HMM) during the steady state of the myosin-ATPase reaction [EC 3.6.1.3] were measured in 1.5 and 0.05M KC1 in the presence of 5mM MgC1(2) and 20mM Tris-HC1 at pH 8.0 and 24 degrees, using pyruvate kinase [EC 2.7.1.40] and phosphoenolpyruvate to regenerate ATP. It was found that the difference spectrum and its dependence on ATP concentration were the same in 1.5M KC1 as in 0.05M KC1. On the bases of these and other results, the nature of the intermediates of HMM ATPase in the steady-state reaction of HMM ATPase was discussed.

Adenosine Triphosphatases↗
PubMed1976

2,4-Dinitrophenol as a specific inhibitor of the breakdown of the actomyosin-phosphate-ADP complex.

2,4-Dinitrophenol (DNP) was found to cause a "clearing response" of myosin B in a medium in which "superprecipitation" of myosin B would otherwise take place. The effect of actin concentration on Mg-ATPase [EC 3.6.1.3] of HMM was studied in the presence and absence of DNP. The results indicate that DNP causes an increase rather than a decrease in the affinity of HMM for actin, and that it causes a decrease only in the actin-activated portion of the Mg-ATPase activity. Using a light-scattering technique, it was shown that neither the ATP-induced dissociation of acto-HMM nor subsequent reassociation is significantly affected by the presence of DNP. As for the formation of the myosin-phosphate-ADP complex in the myosin-ATPase reaction, it was shown that formation of the reactive complex is not affected by DNP. It can thus be concluded that DNP inhibits the decomposition of the actomyosin-phosphate-ADP complex, which is thought to be coupled with superprecipitation.

Actins↗
PubMed1977

Presence of a unit for actin-myosin interaction during the superprecipitation of actomyosin.

The interaction of actin with myosin was studied in the presence of ATP at low ionic strength by means of measurements of the actin-activated ATPase activity of myosin and superprecipitation of actomyosin. At high ATP concentrations the ATPase activities of myosin, heavy meromyosin (HMM) and myosin subfragment 1 (S-1) were activated by actin in the same extent. At low ATP concentrations the myosin ATPase activity was activated about 30-fold by actin, whereas those of HMM and S-1 were stimulated only several-fold. This high actin activation of myosin ATPase was coupled with the occurrence of superprecipitation. The activation of HMM or S-1 ATPase by actin shows a simple hyperbolic dependence on actin concentration, but the myosin ATPase was maximally activated by actin at a 2:1 molar ratio of actin to myosin, and a further increase in the actin concentration had no effect on the activation. These results suggest the presence of a unit for actin-myosin interaction, composed of two actin monomers and one myosin molecule in the filaments.

Actins↗
PubMed1980

Actin-induced local conformational change in the myosin molecule. II. Conformational change around the S2 thiol group related to the essential intermediate of ATP hydrolysis.

The effect of F-actin on the conformation around a specific thiol group, S2, in heavy meromyosin was investigated. The extent of the change was estimated from the residual activity of Ca2+-ATPase after modifying the thiol with N-ethylmaleimide (NEM). Experiments were carried out with a modified heavy meromyosin (HMM), in which S1 had been blocked with NEM, to observe the reactivity of S2 alone. 1. F-Actin markedly increased the ATP-induced conformational change around S2, but did not affect the adenylyl imidodiphosphate (AMPPNP)-induced change, and markedly supressed the adenylyl methylenediphosphate (AMPPCP)-induced change. 2. The initial burst of HMM ATPase was retained after the modification of S1. Replacement of Mg2+ with Mn2+ in the medium reduced the cooperative action of F-actin and ATP with concomitant loss of the initial burst. 3. Nevertheless, F-actin was capable of activating the steady-state ATPase activity of HMM even in the presence of Mn2+. 4. The degree of activation by F-actin of the ATP-induced increase in the reactivity of S2 did not parallel that of the steady-state ATP splitting, when the KCl concentration of the medium was varied. The results indicate that the actin-induced local conformational change in the S2 region is related to an energized state of the myosin molecule caused by Mg2+-ATP, but is apparently not related to the actin-activated steady-state ATPase activity.

Actins↗
PubMed1980

Fluorometric method for estimating the kinetic parameters of beta-naphthyl triphosphate and ATP hydrolysis by acto-heavy meromyosin.

We have established a method to estimate the values of various kinetic parameters of acto-heavy meromyosin (acto-HMM) ATPase, using a fluorescent ATP analog, beta-naphthyl triphosphate (beta-NapP3); from the fluorescence intensity change accompanying beta-NapP3 hydrolysis, the various kinetic parameters of beta-NapP3 hydrolysis, including its product inhibition, were obtained. beta-NapPd3 hydrolysis is inhibited competitively by ATP, resulting in different time courses of fluorescence intensity change in the presence and absence of ATP. From this difference, the values of kinetic parameters of ATP hydrolysis, including its product inhibition, can be estimated. By extending this method to the acto-HMM system, seventeen parameters in a reaction scheme for the concurrent hydrolysis of ATP and beta-NapP3, including association constants between F-actin and substrate-free or substrate-bound HMM, were obtained. The kinetic-parameters estimated for ATP hjydrolsis were in good agreement with those in the literature.

Adenosine Triphosphatases↗
PubMed1980

Earliest event in the heat denaturation of myosin.

In a previous paper (Kimura, I., Arai, K., & Watanabe, S. (1979) J. Biochem. 86, 1629-1638), we reported that when myosin was subjected to heat treatment, inactivation of actomyosin ATPase occurred in two steps; an early fast inactivation, followed by a slow inactivation. A further study was conducted on the fast inactivation in the early stage of heat treatment of myosin, and the following results were obtained: 1. As the weight ratio of actin to heat-treated myosin increased, the rate of early inactivation of actomyosin ATPase increased. 2. The superprecipitation activity of actomyosin was also decreased in two steps by heat treatment of myosin: an early fast inactivation and a subsequent slow inactivation were distinguishable. 3. The turbidity of myosin suspensions in 0.05 M KCl increased during heat treatment of myosin. The increase also proceeded in two distinct steps, and the rate constants for the two steps of increase were comparable to those for inactivation of actomyosin ATPase. 4. In an electron microscopic study, a new change in the morphology of "thick filaments" of myosin was detectable in the early period of heat treatment, when the fast inactivation of actomyosin ATPase was found to occur; myosin filaments were shorter and thinner than the "regular thick filaments" of untreated myosin, and their size was much more heterogeneous. Heterogeneity of myosin aggregates was also detectable in the sedimentation patterns. 5. The actin-binding ability of myosin or HMM remained unaffected during heat treatment of myosin. The binding ability was estimated in three different ways; by measuring the ATP-induced changed in the turbidity of actomyosin solution, the actin-inhibition of EDTA-ATPase of myosin, and the actin-activation of Mg-ATPase of HMM. 6. In a sedimentation study, formation of myosin dimers was not detectable in the early period of heat treatment of myosin, and was detectable only in the later period. Likewise, increase in the light scattering intensity of myosin solutions occurred only in the later period of heat treatment of myosin. 7. Heat treatment caused a decrease in the ATP-induced enhancement of the HMM fluorescence. The decrease was fitted by a single exponential (first-order reaction), and not by two exponentials. 8. Heat-induced change was not detectable either in the light scattering intensity of LMM solutions in 0.5 M KCl or in the turbidity of LMM suspensions in 0.05 M KCl. Based on these results, it is strongly suggested that the earliest event in heat denaturation of myosin is loss of the ability of myosin to form "regular thick filaments."

Actins↗
PubMed2006

ECG signal analysis through hidden Markov models.

This paper presents an original hidden Markov model (HMM) approach for online beat segmentation and classification of electrocardiograms. The HMM framework has been visited because of its ability of beat detection, segmentation and classification, highly suitable to the electrocardiogram (ECG) problem. Our approach addresses a large panel of topics some of them never studied before in other HMM related works: waveforms modeling, multichannel beat segmentation and classification, and unsupervised adaptation to the patient's ECG. The performance was evaluated on the two-channel QT database in terms of waveform segmentation precision, beat detection and classification. Our waveform segmentation results compare favorably to other systems in the literature. We also obtained high beat detection performance with sensitivity of 99.79% and a positive predictivity of 99.96%, using a test set of 59 recordings. Moreover, premature ventricular contraction beats were detected using an original classification strategy. The results obtained validate our approach for real world application.

Artificial Intelligence↗
PubMedDate not supplied

A hidden Markov model for transcriptional regulation in single cells.

We discuss several issues pertaining to the use of stochastic biochemical systems for modeling transcriptional regulation in single cells. By appropriately choosing the system state, we can model transcriptional regulation by a hidden Markov model (HMM). This opens the possibility of using well-known techniques for the statistical analysis and stochastic control of HMMs to mathematically and computationally study transcriptional regulation in single cells. Unfortunately, in all but a few simple cases, analytical characterization of the statistical behavior of the proposed HMM is not possible. Moreover, analysis by Monte Carlo simulation is computationally cumbersome. We discuss several techniques for approximating the HMM by one that is more tractable. We employ simulations, based on a biologically relevant transcriptional regulatory system, to show the relative merits and limitations of various approximation techniques and provide general guidelines for their use.

Cell Physiological Phenomena↗
PubMed2006

Prediction for human motion tracking failures.

We propose a new and effective method of predicting tracking failures and apply it to the robust analysis of gait and human motion. We define a tracking failure as an event and describe its temporal characteristics using a hidden Markov model (HMM). We represent the human body using a three-dimensional, multicomponent structural model, where each component is designed to independently allow the extraction of certain gait variables. To enable a fault-tolerant tracking and feature extraction system, we introduce a single HMM for each element of the structural model, trained on previous examples of tracking failures. The algorithm derives vector observations for each Markov model using the time-varying noise covariance matrices of the structural model parameters. When transformed with a logarithmic function, the conditional output probability of each HMM is shown to have a causal relationship with imminent tracking failures. We demonstrate the effectiveness of the proposed approach on a variety of multiview video sequences of complex human motion.

Algorithms↗
PubMed2005

Multi-aspect target discrimination using hidden Markov models and neural networks.

This paper presents a new multi-aspect pattern classification method using hidden Markov models (HMMs). Models are defined for each class, with the probability found by each model determining class membership. Each HMM model is enhanced by the use of a multilayer perception (MLP) network to generate emission probabilities. This hybrid system uses the MLP to find the probability of a state for an unknown pattern and the HMM to model the process underlying the state transitions. A new batch gradient descent-based method is introduced for optimal estimation of the transition and emission probabilities. A prediction method in conjunction with HMM model is also presented that attempts to improve the computation of transition probabilities by using the previous states to predict the next state. This method exploits the correlation information between consecutive aspects. These algorithms are then implemented and benchmarked on a multi-aspect underwater target classification problem using a realistic sonar data set collected in different bottom conditions.

Discriminant Analysis↗