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Results for “trajectory analysis”

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PubMed1986

Dynamics of accommodation: measurements for clinical application.

Accommodation dynamics have not been used in clinical diagnosis as have eye movement and pupillary dynamics; the difficulty of clinical observation is matched by limitations in measurement methods. An instrument suitable for clinical use is described that allows measurement of step response latencies and especially time constants. With computer analysis, phase plane trajectories, and noise spectra can be quickly obtained also. The utility of these dynamical parameters for clinical diagnosis is illustrated by a study of changes of time constants with age in prepresbyopia.

Accommodation, Ocular↗

PubMed1993

Proximal and distal impairments in rat forelimb use in reaching follow unilateral pyramidal tract lesions.

Although it was once thought that the corticospinal (pyramidal) tract was the main substrate of voluntary movement, the extent to which it is involved in the control of proximal vs. distal musculature, independent finger movements, and movements characteristic of different species of animals now is unclear. The objective of this study was to examine the effects of pyramidal tract lesions on skilled forelimb use in rats. In addition, cell morphology in motor cortex following lesions was examined. Naive and trained rats received unilateral pyramidal sections just rostral to the pyramidal decussation. Performance was assessed and filmed on two reaching tasks. Measures of reaching consisted of success in obtaining food, kinematic analysis of limb trajectory and velocity, and qualitative evaluation of 10 movement components comprising a reach. Pyramidal tract lesions only impaired reaching for single food pellets. Almost all movements comprising a reach, except digit opening, were impaired, including lifting, aiming, pronating and supinating the limb, and releasing food. Although success in limb use was unchanged over the 180 day observation period, there were significant improvements in the qualitative features of limb use. Histologically, the morphology of pyramidal cells in the forelimb area ipsilateral to the lesion seemed normal. Rats with additional damage to adjacent structures, such as the medial lemniscus and olivary complex, were much more severely impaired on the reaching tasks, and displayed similar impairments as judged by qualitative and kinematic measures. The results demonstrate that a number of movements involved in independent limb use are chronically impaired by pyramidal tract lesions in the rat. Nevertheless, significant use of the limb is possible, due perhaps to both the contribution of extrapyramidal motor systems and the influence of the remaining pyramidal system through its extrapyramidal connections. The results not only show that the rat pyramidal tract supports functions very similar to those of primates and thus might provide a good model for some aspects of pyramidal tract dysfunctions, but also they argue that the pyramidal tract is involved in both proximal and distal limb movements.

Animals↗

PubMed2004

Rehabilitation of reaching after stroke: task-related training versus progressive resistive exercise.

OBJECTIVE: To evaluate the effectiveness of 2 rehabilitative approaches for improving paretic limb reaching by chronic stroke subjects. DESIGN: Pre- and posttest reaching to targets ipsilateral, midline, and contralateral to the impaired side. SETTING: Training in subjects' homes; testing in a laboratory setting. PARTICIPANTS: Twelve poststroke volunteers were matched using the Motor Assessment Scale (MAS) and then were randomly assigned to 1 of 2 training conditions. Subjects were subsequently categorized as at a high or low functional level, using the reaching pretest movement time scores. INTERVENTIONS: Training (trunk unrestrained) using the paretic limb was 4 weeks (12 sessions). Task-related training (TRT) involved reaching to objects placed across the workspace. Progressive resistive exercise (PRE) involved whole-arm pulling against resistive therapeutic tubing in planes and distances similar to that in TRT. Main outcome measures Kinematic analysis of arm trajectory and trunk motion using the Peak Performance System, as well as scores on the MAS and the Rivermead Motor Assessment (RMA). RESULTS: For low-level groups, TRT resulted in increased substitutive trunk use at the target ipsilateral to the moving arm, and for midline and contralateral targets after PRE. Only low-level, TRT subjects straightened hand paths, which suggested better coordination of elbow-shoulder motion, and improved on the RMA. High-level subjects decreased trunk use at ipsilateral target after PRE, which was not observed after TRT. No significant differences between training conditions were found for other kinematic variables. CONCLUSIONS: Training benefits appear to depend on initial level of functioning. Although compensatory trunk use was evident, low-level subjects seemed to benefit most from TRT. High-level subjects, whose kinematics showed fairly normal movement organization, demonstrated less compensatory movement after PRE.

Aged↗

PubMed2005

Computing spike directivity with tetrodes.

The ability of neurons to generate electrical signals is strongly dependent on the evolution of ion-specific pumps and channels that allow the transfer of charges under the influence of electric fields and concentration gradients. This paper presents a novel method by which flow of these charge fluxes may be computed to provide directivity of charge movement. Simulations of charge flow as well as actual electrophysiological data recorded by tetrodes are used to demonstrate the method. The propagation of charge fluxes in space in data from simulation and actual recordings during action potential can be analyzed using signals recorded by tetrodes. Variation in spike directivity can be estimated by computing singular value decomposition of the estimated 3D trajectory data. The analysis of the spike model can be accomplished by performing simulations of presumed equivalent moving charges recorded by the tetrode tips. For in vivo spike recordings, the variation of spike directivity could be obtained using several spikes of selected neurons considering the charge movement model (CMM). The relationship between computer simulation results and tetrode data recordings is examined. The paper concludes by showing that the method for calculating directivity in actual spike recordings is robust. The method allows for improved filtering of data and more importantly may shed light on furthering the study of spatio-temporal encoding in neurons.

Action Potentials↗

PubMed2001

Understanding beta-hairpin formation by molecular dynamics simulations of unfolding.

We have studied the mechanism of formation of a 16-residue beta-hairpin from the protein GB1 using molecular dynamics simulations in an aqueous environment. The analysis of unfolding trajectories at high temperatures suggests a refolding pathway consisting of several transient intermediates. The changes in the interaction energies of residues are related with the structural changes during the unfolding of the hairpin. The electrostatic energies of the residues in the turn region are found to be responsible for the transition between the folded state and the hydrophobic core state. The van der Waals interaction energies of the residues in the hydrophobic core reflect the behavior of the radius of gyration of the core region. We have examined the opposing influences of the protein-protein (PP) energy, which favors the native state, and the protein-solvent (PS) energy, which favors unfolding, in the formation of the beta-hairpin structure. It is found that the behavior of the electrostatic components of PP and PS energies reflects the structural changes associated with the loss of backbone hydrogen bonding. Relative changes in the PP and PS van der Waals interactions are related with the disruption of the hydrophobic core of a protein. The results of the simulations support the hydrophobic collapse mechanism of beta-hairpin folding.

Animals↗

PubMed2002

Molecular dynamics simulation of the RNA complex of a double-stranded RNA-binding domain reveals dynamic features of the intermolecular interface and its hydration.

The interaction between double-stranded RNA (dsRNA) and the third double-stranded domain (dsRBD) from Drosophila Staufen protein represents a paradigm to understand how the dsRBD protein family, one of the most common RNA-binding protein units, binds dsRNA. The nuclear magnetic resonance (NMR) structure of this complex and the x-ray structure of another family member revealed the stereochemical basis for recognition, but also raised new questions. Although the crystallographic studies revealed a highly ordered interface containing numerous water-mediated contacts, NMR suggested extensive residual motion at the interface. To address how interfacial motion contributes to molecular recognition in the dsRBD-dsRNA system, we conducted a 2-ns molecular dynamics simulation of the complex derived from Staufen protein and of the separate protein and RNA components. The results support the observation that a high degree of conformational flexibility is retained upon complex formation and that this involves interfacial residues that are critical for dsRBD-dsRNA binding. The structural origin of this residual flexibility is revealed by the analysis of the trajectory of motion. Individual basic side chains switch continuously from one RNA polar group to another with a residence time seldom exceeding 100 ps, while retaining favorable interaction with RNA throughout much of the simulation. Short-lived water molecules mediate some of these interactions for a large fraction of the trajectory studied here. This result indicates that water molecules are not statically associated with the interface, but continuously exchange with the bulk solvent on a 1-10-ps time scale. This work provides new insight into dsRBD-dsRNA recognition and builds upon a growing body of evidence, suggesting that short-lived dynamic interactions play important roles in protein-nucleic acid interactions.

Binding Sites↗

PubMed1998

Molecular dynamics simulations of individual alpha-helices of bacteriorhodopsin in dimyristoylphosphatidylcholine. II. Interaction energy analysis.

The concepts of hydrophobicity and hydrophobic moments have been applied in attempts to predict membrane protein secondary and tertiary structure. The current paper uses molecular dynamics computer calculations of individual bacteriorhodopsin helices in explicit dimyristoylphosphatidylcholine bilayers to examine the atomic basis of these approaches. The results suggest that the types of interactions between a particular amino acid and the surrounding bilayer depend on the position and type of the amino acid. In particular, aromatic residues are seen to interact favorably at the interface region. Analysis of the trajectories in terms of hydrophobic moments suggests the presence of a particular face that prefers lipid. The results of these simulations may be used to improve secondary structure prediction methods and to provide further insights into the two-stage model of protein folding.

Amino Acids↗

PubMed2002

Motion of an antiviral compound in a rhinovirus capsid under rotational symmetry boundary conditions.

A molecular dynamics (MD) simulation of a complex of a rhinovirus protein shell referred to as a "capsid" and an anti-rhinovirus drug, WIN52084s, was performed under the rotational symmetry boundary conditions. For the simulation, the energy parameters of WIN52084s in all-atom approximations were determined by ab initio calculations using a 6-31G* basis set and the two-conformational two-stage restricted electrostatic potential fit method. The motion of WIN52084s and the capsid was focused on in the analysis of the trajectory of the simulation. The root mean square deviations of WIN52084s from the X-ray structure were decomposed to conformational, translational, and rotational components. The translation was further decomposed to radial, longitudinal, and lateral components. The conformation of WIN52084s was rigid, but moving in the pocket. The easiest path of motion for WlN52084s was on the longitudinal line, providing a track for the binding process required of the anti-rhinovirus drug to enter the pocket. The conformation of the pocket was also preserved in the simulation, although the position of the pocket in the capsid fluctuated in the lateral and radial directions.

Antiviral Agents↗

PubMed2001

Theoretical studies of d(A:T)-based parallel-stranded DNA duplexes.

Poly d(A:T) parallel-stranded DNA duplexes based on the Hoogsteen and reverse Watson-Crick hydrogen bond pairing are studied by means of extensive molecular dynamics (MD) simulations and molecular mechanics coupled to Poisson-Boltzmann (MM-PB/SA) calculations. The structural, flexibility, and reactivity characteristics of Hoogsteen and reverse Watson-Crick parallel duplexes are described from the analysis of the trajectories. Theoretical calculations show that the two parallel duplexes are less stable than the antiparallel Watson-Crick duplex. The difference in stability between antiparallel and parallel duplexes increases steadily as the length of the duplex increases. The reverse Watson-Crick arrangement is slightly more stable than the Hoogsteen duplex, the difference being also increased linearly with the length of the duplex. A subtle balance of intramolecular and solvation terms is responsible for the preference of a given helical structure.

DNA↗

PubMed2004

Ab initio molecular dynamics simulations and g-tensor calculations of aqueous benzosemiquinone radical anion: effects of regular and "T-stacked" hydrogen bonds.

Car-Parrinello molecular dynamics (CP-MD) simulations of the benzosemiquinone radical anion in aqueous solution have been performed at ambient conditions. Analysis of the trajectory shows not only extensive hydrogen bonding to the carbonyl oxygen atoms (ca. 4-5.6 water molecules depending on distance criteria), but also relatively long-lived "T-stacked" hydrogen bonds to the semiquinone pi-system. These results are discussed in the context of recent findings on semiquinone-protein interactions in photosynthetic reaction centers, and of EPR and vibration spectroscopical data for the aqueous system. Snapshots from the CP-MD trajectory are used for the first quantum chemical analyses of dynamical effects on electronic g-tensors, using cluster models and a recently developed density functional method. In particular, the effects of intermolecular hydrogen-bond dynamics on the g-tensor components are examined, in comparison with recent EPR and ENDOR studies.

Benzoquinones↗

PubMed2005

Structure and dynamics of solvated Sn(II) in aqueous solution: an ab initio QM/MM MD approach.

Structural and dynamical properties of the hydrated Sn(II) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at double-zeta HF quantum mechanical level. The results indicate Sn(II)aq to be a rather peculiar, if not unique, case of a hydrated ion: four of its eight first-shell ligands do not take place in the otherwise frequent ligand-exchange processes, forming an approximately tetrahedral cage around the ion. The remaining ligands, however, exchange at a rate that is rather comparable to monovalent than divalent ions. This very surprising behavior of ligand exchange not yet observed in any previous simulation of over 30 hydrated metal ions is consistently confirmed by vibrational spectra, bond lengths, and a detailed analysis of the trajectories of the simulation.

Computer Simulation↗

PubMed1999

Binding preferences of hydroxamate inhibitors of the matrix metalloproteinase human fibroblast collagenase.

In this paper we report molecular dynamics (MD) and free energy perturbation (FEP) studies carried out on enzyme-inhibitor (two hydroxamates that only differ by a carbon-carbon double bond) complexes of human fibroblast collagenase to obtain insights into the structural and energetic preferences of these inhibitors. We have developed a bonded model for the catalytic and structural zinc centers (Hoops, S. C.; et al. J. Am. Chem. Soc. 1991, 113, 8262-8270) where the electrostatic representation for this model was derived using a novel quantum-mechanical/molecular-mechanical (QM/MM) minimization procedure followed by electrostatic potential fitting. The resulting bonded model for the zinc ions was then used to generate MD trajectories for structural analysis and FEP studies. This model has satisfactorily reproduced the structural features of the active site, and furthermore, the FEP simulations gave relative free energies of binding in good agreement with experimental results. MD simulations in conjunction with the FEP are able to provide a structural explanation regarding why one hydroxamate inhibitor is favored over the other, and we are also able to make predictions about changes in the inhibitor that would enhance protein-inhibitor interactions.

Binding Sites↗

PubMed2005

MD simulation of the Na+-phenylalanine complex in water: competition between cation-pi interaction and aqueous solvation.

The competition between cation-pi interaction and aqueous solvation for the Na+ ion has been investigated by molecular dynamics simulations, using the phenylalanine amino acid as the test pi system. Starting from one of the best standard force fields, we have developed new parameters that significantly improve the agreement with experimental and high quality quantum mechanical results for the complexes of Na+ with phenylalanine, benzene, and water. The modified force field performs very well in forecasting energy and geometry of cation coordination for the complexes. Next, analysis of MD trajectories and steered MD simulations indicate that the Na+-phenylalanine complex survives for a significant time in aqueous solution and that the free energy barrier opposing dissociation of the complex is sizable. Finally, we analyze the role of different intermolecular interactions in determining the preference for cation-pi bonding with respect to aqueous solvation. We thus confirm that the Na+-phenylalanine stabilization energy may overcome the interactions with water.

Journal Article↗

PubMed2006

Modulation of amphotericin B membrane interaction by cholesterol and ergosterol--a molecular dynamics study.

Amphotericin B (AmB) is a well-known polyene macrolide antibiotic used to treat systemic fungal infections. According to a well-documented hypothesis, molecules of AmB form ionic membrane channels that are responsible for chemotherapeutic action. These channels disturb the barrier function of the cell membrane which, in consequence, leads to cell death. The presence of sterols in the cell membrane is necessary for full manifestation of the antibiotic's ionophoric activity, at least in vivo. Ergosterol-containing fungal membranes are targeted more efficiently by AmB than mammalian membranes containing cholesterol. However, a similar level of disturbance of fungal and mammalian membranes is responsible for serious toxicity of the antibiotic. Due to the importance of AmB and lack of better antifungal alternatives, the search for new less toxic derivatives of this antibiotic still continues. Therefore, studies of the AmB-membrane interaction are very important. The present work constitutes a continuation of a broad program of study on AmB mode of action in our group. In particular, molecular dynamics simulations of AmB monomers inside the bilayers of three different compositions (pure dimiristoylphosphatidylcholine (DMPC) and DMPC bilayer containing approximately 25 mol % of cholesterol or ergosterol) were carried out. In general, analysis of generated trajectories resulted in identifying many significant differences in the behavior of AmB monomers depending on the membrane environment. In particular, it was established that the antibiotic increases the internal order of DMPC bilayer containing 25 mol % of cholesterol, while it has no effect on the order of the bilayer with the same amount of ergosterol. Performed calculations also revealed that relatively rigid and elongated AmB molecules exhibit higher affinity toward the sterol-containing lo phases and, therefore, may be cumulated in ordered membrane domains (e.g., lipid rafts). Since the partition coefficient between the ld and lo phase appears to be greater in the case of the ergosterol- compared to cholesterol-containing membrane, this effect can be also discussed as the possible origin of AmB-selective toxicity and indirect sterol involvement in expression of AmB activity.

Amphotericin B↗

PubMed1996

Polar fluctuations in proteins: molecular-dynamic studies of cytochrome c in aqueous solution.

The equilibrium fluctuations (the polar fluctuations), of yeast cytochrome c are studied using nanosecond molecular-dynamic simulations in a spherical droplet of water, with a particular emphasis on the fluctuations of the total dipole moment, which determine the average relative permittivity. These fluctuations follow a simple probability distribution, predicted by continuum electrostatics, and already observed in simulations of several polar liquids. An important component consists of diffusive, mutually independent, motions of the charged side chains at the protein surface. A quasiharmonic normal mode analysis of the trajectory shows that while motions covering a large range of frequencies contribute to the polar fluctuations, the four lowest frequency modes account for 50% of the overall static relative permittivity of ca. 25. The fluctuations of the protein bulk, i.e. parts other than the charged side chains, are distributed over a larger number of modes. Modes up to at least 60 cm-1 contribute to the average relative permittivity of the protein interior of ca. 4. The water surrounding the protein, despite the structural perturbation represented by the protein, has fluctuations similar to pure water, consistent with the idea of a linear solvent response to the protein charges. The relationship between the microscopic fluctuations seen in the simulations and simple continuum models is discussed.

Cytochrome c Group↗

PubMed1992

Quantitative description of the dysarthria in women with amyotrophic lateral sclerosis.

Speech intelligibility and its phonetic and acoustic correlates were studied in a group of 10 women with amyotrophic lateral sclerosis (ALS). Intelligibility assessment with a word-identification test indicated that the most disrupted phonetic features pertained to velopharyngeal valving, lingual function for consonant contrasts of place and manner, and syllable shape. An acoustic signature analysis based on trajectories of the first and second formants in selected monosyllabic test words revealed that the mean slope of the second formant (F2) was reduced compared with that of a normal geriatric control group. This F2 slope reduction is interpreted to reflect loss of lingual motoneurons. Acoustic measures of phonatory function for sustained vowel prolongation demonstrated abnormalities in fundamental frequency, perturbations of frequency (jitter) and amplitude (shimmer), and signal-to-noise ratio. The data for women with ALS are compared with data for a normal geriatric control group of women and with data for a group of 25 men with ALS (Kent et al., 1990). Although the overall ranking of errors was similar for males and females with ALS, men were more likely to have impairments of voicing in syllable-initial position.

Adult↗

PubMed2005

Transient electric birefringence of wormlike macromolecules in electric fields of arbitrary strength: a computer simulation study.

We have studied the birefringence decay of linear models of macromolecules for two different types of flexibility, the broken-rod chain and the wormlike chain, using a computer simulation of a transient electric birefringence experiment. We have paid particular attention to the influence of the intensity of the orienting field, including two orienting mechanisms, the induced dipole, and the permanent dipole. We have compared wormlike and broken-rod models of the same radius of gyration, finding that they present a different decay curve under the influence of the same intensity of the field. We have seen that these differences are due to the faster relaxation times (smaller in the wormlike chain model) and amplitudes, because, regardless of the type of flexibility, the overall size of a molecule (measured by the radius of gyration) essentially determines the longest relaxation time. We have also analyzed how the relaxation process is affected by the degree of flexibility, the orientation mechanisms, and the intensity of the field. Studying a different aspect, we have paid attention to the deformation of a molecule in a transient electric birefringence experiment as a source of information. In this work we have developed equations to characterize this deformation in terms of one of the components of the gyration tensor, if a dynamic light scattering experiment under the influence of an electric field could be performed. To develop this work we have simulated the Brownian dynamics of the different models, relaxing after the removal of an orienting external electric field of arbitrary strength. A comparison with other methods such a the rigid body treatment or the correlation analysis of Brownian trajectories has also been included. We have seen that differences between the two Brownian dynamics methods are small and that the rigid-body treatment is only an acceptable approximation to obtain the longest relaxation time.

Journal Article↗

PubMed2002

An atomically detailed study of the folding pathways of protein A with the stochastic difference equation.

An algorithm is applied here to compute folding pathways of staphylococcal protein A, fragment B. Emphasis is on studies of the complete process, starting from an ensemble of fully denatured conformations and ending at the folded state. The stochastic difference equation algorithm is based on optimization of an action that makes it possible to use a large integration step. Motions with typical displacements that change rapidly on the size scale of the step are filtered out, providing numerically stable and approximate solutions. The present approach is unique in maintaining an atomically detailed picture while providing a systematic, controlled approximation to the classical equations of motion. Analysis of 130 trajectories suggests the following folding mechanism for protein A: At an early precollapse phase of the process, a few native hydrogen bonds form near the C terminus of the protein. The hydrogen bonds are formed mostly within the third helix. The next step is chain collapse that occurs in parallel to additional growth of secondary structure seeds. Therefore, the present study does not support a pure hydrophobic collapse, or substantial early formation of secondary structure. At the last step, native tertiary contacts are formed at the same time as the completion of the secondary structure elements. To a large extent, the process is parallel and not sequential. The early formation of the third helix of protein A, fragment B (in the calculation), is consistent with experimental data.

Algorithms↗