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Biomedical subjects

Kaihsu Tai

Publications and source records attributed to Kaihsu Tai.

14 recordsLinked to original sources
PubMed2006

Three hydrolases and a transferase: comparative analysis of active-site dynamics via the BioSimGrid database.

Comparative molecular dynamics (MD) simulations enable us to explore the conformational dynamics of the active sites of distantly related enzymes. We have used the BioSimGrid (http://www.biosimgrid.org) database to facilitate such a comparison. Simulations of four enzymes were analyzed. These included three hydrolases and a transferase, namely acetylcholinesterase, outer-membrane phospholipase A, outer-membrane protease T, and PagP (an outer-membrane enzyme which transfers a palmitate chain from a phospholipid to lipid A). A set of 17 simulations were analyzed corresponding to a total of approximately 0.1 micros simulation time. A simple metric for active-site integrity was used to demonstrate the existence of clusters of dynamic conformational behaviour of the active sites. Small (i.e. within a cluster) fluctuations appear to be related to the function of an enzymatically active site. Larger fluctuations (i.e. between clusters) correlate with transitions between catalytically active and inactive states. Overall, these results demonstrate the potential of a comparative MD approach to analysis of enzyme function. This approach could be extended to a wider range of enzymes using current high throughput MD simulation and database methods.

Acetylcholinesterase↗
PubMed2005

Grid computing and biomolecular simulation.

Biomolecular computer simulations are now widely used not only in an academic setting to understand the fundamental role of molecular dynamics on biological function, but also in the industrial context to assist in drug design. In this paper, two applications of Grid computing to this area will be outlined. The first, involving the coupling of distributed computing resources to dedicated Beowulf clusters, is targeted at simulating protein conformational change using the Replica Exchange methodology. In the second, the rationale and design of a database of biomolecular simulation trajectories is described. Both applications illustrate the increasingly important role modern computational methods are playing in the life sciences.

Biopolymers↗
PubMed2005

Molecular dynamics simulation of the M2 helices within the nicotinic acetylcholine receptor transmembrane domain: structure and collective motions.

Multiple nanosecond duration molecular dynamics simulations were performed on the transmembrane region of the Torpedo nicotinic acetylcholine receptor embedded within a bilayer mimetic octane slab. The M2 helices and M2-M3 loop regions were free to move, whereas the outer (M1, M3, M4) helix bundle was backbone restrained. The M2 helices largely retain their hydrogen-bonding pattern throughout the simulation, with some distortions in the helical end and loop regions. All of the M2 helices exhibit bending motions, with the hinge point in the vicinity of the central hydrophobic gate region (corresponding to residues alphaL251 and alphaV255). The bending motions of the M2 helices lead to a degree of dynamic narrowing of the pore in the region of the proposed hydrophobic gate. Calculations of Born energy profiles for various structures along the simulation trajectory suggest that the conformations of the M2 bundle sampled correspond to a closed conformation of the channel. Principal components analyses of each of the M2 helices, and of the five-helix M2 bundle, reveal concerted motions that may be relevant to channel function. Normal mode analyses using the anisotropic network model reveal collective motions similar to those identified by principal components analyses.

Amino Acid Sequence↗
PubMed2004

Not ions alone: barriers to ion permeation in nanopores and channels.

A hydrophobic pore of subnanometer dimensions can appear impermeable to an ion even though its radius is still much wider than that of the ion. Pores of molecular dimensions can be found, for instance, in carbon nanotubes, zeolites, or ion channel proteins. We quantify this barrier to ion permeation by calculating the potential of mean force from umbrella-sampled molecular dynamics simulations and compare them to continuum-electrostatic Poisson-Boltzmann calculations. The latter fail to describe the ion barrier because they do not account for the properties of water in the pore. The barrier originates from the energetic cost to desolvate the ion. Even in wide pores, which could accommodate an ion and its hydration shell, a barrier of several kT remains because the liquid water phase is not stable in the hydrophobic pore. Thus, the properties of the solvent play a crucial role in determining permeation properties of ions in confinement at the molecular scale.

Journal Article↗
PubMed2004

BioSimGrid: towards a worldwide repository for biomolecular simulations.

BioSimGrid is a database for biomolecular simulations, or, a "Protein Data Bank extended in time" for molecular dynamics trajectories. We describe the implementation details: architecture, data schema, deposition, and analysis modules. We encourage the simulation community to explore BioSimGrid and work towards a common trajectory exchange format.

Acetylcholinesterase↗
PubMed2004

Acetylcholinesterase: enhanced fluctuations and alternative routes to the active site in the complex with fasciculin-2.

A 15 ns molecular dynamics simulation is reported for the complex of mouse acetylcholinesterase (mAChE) and the protein neurotoxin fasciculin-2. As compared to a 15 ns simulation of apo-mAChE, the structural fluctuations of the enzyme are substantially increased in magnitude for the enzyme in the complex. Fluctuations of part of the long omega loop (residues 69-96) are particularly enhanced. This loop forms one wall of the active site, and the enhanced fluctuations lead to additional routes of access to the active site.

Acetylcholinesterase↗
PubMed2004

Conformational sampling for the impatient.

Several new methods for sampling conformations of biomolecules have appeared recently. A brief review thereof is presented, with particular emphasis on applications that have been published, and suitability for different kinds of systems. Four methods (namely: RESPA, replica-exchange molecular dynamics, CONCOORD and Gaussian network method) are readily applicable for biomolecular systems.

Algorithms↗
PubMed2003

Nanosecond dynamics of the mouse acetylcholinesterase cys69-cys96 omega loop.

The paradox of high substrate turnover occurring within the confines of a deep, narrow gorge through which acetylcholine must traverse to reach the catalytic site of acetylcholinesterase has suggested the existence of transient gorge enlargements that would enhance substrate accessibility. To establish a foundation for the experimental study of transient fluctuations in structure, site-directed labeling in conjunction with time-resolved fluorescence anisotropy were utilized to assess the possible involvement of the omega loop (Omega loop), a segment that forms the outer wall of the gorge. Specifically, the flexibility of three residues (L76C, E81C, and E84C) in the Cys69-Cys96 Omega loop and one residue (Y124C) across the gorge from the Omega loop were studied in the absence and presence of two inhibitors of different size, fasciculin and huperzine. Additionally, to validate the approach molecular dynamics was employed to simulate anisotropy decay of the side chains. The results show that the Omega loop residues are significantly more mobile than the non-loop residue facing the interior of the gorge. Moreover, fasciculin, which binds at the mouth of the gorge, well removed from the active site, decreases the mobility of 5-((((2-acetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid reporter groups attached to L76C and Y124C but increases the mobility of the reporter groups attached to E81C and E84C. Huperzine, which binds at the base of active-site gorge, has no effect on the mobility of reporter groups attached to L76C and Y124C but increases the mobility of the reporter groups attached to E81C and E84C. Besides showing that fluctuations of the Omega loop residues are not tightly coupled, the results indicate that residues in the Omega loop exhibit distinctive conformational fluctuations and therefore are likely to contribute to transient gorge enlargements in the non-liganded enzyme.

Acetylcholinesterase↗
PubMed2003

Finite element simulations of acetylcholine diffusion in neuromuscular junctions.

A robust infrastructure for solving time-dependent diffusion using the finite element package FEtk has been developed to simulate synaptic transmission in a neuromuscular junction with realistic postsynaptic folds. Simplified rectilinear synapse models serve as benchmarks in initial numerical studies of how variations in geometry and kinetics relate to endplate currents associated with fast-twitch, slow-twitch, and dystrophic muscles. The flexibility and scalability of FEtk affords increasingly realistic and complex models that can be formed in concert with expanding experimental understanding from electron microscopy. Ultimately, such models may provide useful insight on the functional implications of controlled changes in processes, suggesting therapies for neuromuscular diseases.

Acetylcholine↗
PubMed2002

Mechanism of acetylcholinesterase inhibition by fasciculin: a 5-ns molecular dynamics simulation.

Our previous molecular dynamics simulation (10 ns) of mouse acetylcholinesterase (EC 3.1.1.7) revealed complex fluctuation of the enzyme active site gorge. Now we report a 5-ns simulation of acetylcholinesterase complexed with fasciculin 2. Fasciculin 2 binds to the gorge entrance of acetylcholinesterase with excellent complementarity and many polar and hydrophobic interactions. In this simulation of the protein-protein complex, where fasciculin 2 appears to sterically block access of ligands to the gorge, again we observe a two-peaked probability distribution of the gorge width. When fasciculin is present, the gorge width distribution is altered such that the gorge is more likely to be narrow. Moreover, there are large increases in the opening of alternative passages, namely, the side door (near Thr 75) and the back door (near Tyr 449). Finally, the catalytic triad arrangement in the acetylcholinesterase active site is disrupted with fasciculin bound. These data support that, in addition to the steric obstruction seen in the crystal structure, fasciculin may inhibit acetylcholinesterase by combined allosteric and dynamical means. Additional data from these simulations can be found at http://mccammon.ucsd.edu/.

Acetylcholinesterase↗
PubMed2002

Properties of water molecules in the active site gorge of acetylcholinesterase from computer simulation.

A 10-ns trajectory from a molecular dynamics simulation is used to examine the structure and dynamics of water in the active site gorge of acetylcholinesterase to determine what influence water may have on its function. While the confining nature of the deep active site gorge slows down and structures water significantly compared to bulk water, water in the gorge is found to display a number of properties that may aid ligand entry and binding. These properties include fluctuations in the population of gorge waters, moderate disorder and mobility of water in the middle and entrance to the gorge, reduced water hydrogen-bonding ability, and transient cavities in the gorge.

Acetylcholinesterase↗
PubMed2002

Molecular dynamics of acetylcholinesterase.

Molecular dynamics simulations are leading to a deeper understanding of the activity of the enzyme acetylcholinesterase. Simulations have shown how breathing motions in the enzyme facilitate the displacement of substrate from the surface of the enzyme to the buried active site. The most recent work points to the complex and spatially extensive nature of such motions and suggests possible modes of regulation of the activity of the enzyme.

Acetylcholinesterase↗
PubMedDate not supplied

The alpha7 nicotinic acetylcholine receptor: molecular modelling, electrostatics, and energetics.

The structure of a homopentameric alpha7 nicotinic acetylcholine receptor is modelled by combining structural information from two sources: the X-ray structure of a water soluble acetylcholine binding protein from Lymnea stagnalis, and the electron microscopy derived structure of the transmembrane domain of the Torpedo nicotinic receptor. The alpha7 nicotinic receptor model is generated by simultaneously optimising: (i) chain connectivity, (ii) avoidance of stereochemically unfavourable contacts, and (iii) contact between the beta1-beta2 and M2-M3 loops that have been suggested to be involved in transmission of conformational change between the extracellular and transmembrane domains. A Gaussian network model was used to predict patterns of residue mobility in the alpha7 model. The results of these calculations suggested a flexibility gradient along the transmembrane domain, with the extracellular end of the domain more flexible that the intracellular end. Poisson-Boltzmann (PB) energy calculations and atomistic (molecular dynamics) simulations were used to estimate the free energy profile of a Na+ ion as a function of position along the axis of the pore-lining M2 helix bundle of the transmembrane domain. Both types of calculation suggested a significant energy barrier to exist in the centre of the (closed) pore, consistent with a "hydrophobic gating" model. Estimations of the PB energy profile as a function of ionic strength suggest a role of the extracellular domain in determining the cation selectivity of the alpha7 nicotinic receptor. These studies illustrate how molecular models of members of the nicotinic receptor superfamily of channels may be used to study structure-function relationships.

Amino Acid Sequence↗