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Winner of the IUPAC Prize
for Young Chemists - 2003

Kaihsu Tai wins one of the 5 IUPAC Prize for Young Chemists, for his Ph.D. thesis work entitled "Simulations of molecules and processes in the synapse."

Current address

University of Oxford
Rex Richards Building
South Parks Road
Oxford OX1 3QU

Academic degrees

  • Ph.D. in Chemistry, University of California, San Diego, CA, USA, Dec 2002
  • M.S. in Chemistry, University of California, San Diego, CA, USA, June 2000
  • B.S. with Honor, in Chemistry, Caltech, Pasadena, CA, USA, June 1998
  • Ph.D. Thesis

    Title Simulations of molecules and processes in the synapse.
    Adviser Prof. J. Andrew McCammon
    Thesis Committee Elizabeth A. Komives, Chemistry and Biochemistry; John C. Wheeler, Chemistry and Biochemistry, Michael Jay Holst, Mathematics; and Palmer W. Taylor, Pharmacology, UCSD


Computer simulation in biochemistry. With the development of both theory and computer technology, simulation has become a viable way of investigating the behavior of biomolecules. First applied to proteins 25 years ago by McCammon and coworkers, the method of Newtonian molecular dynamics has now entered the mainstream of biochemistry. Recently, mesoscale and multiscale methods have emerged, with the promise of bringing up the scale of simulations from molecular level to organellar and even cellular level.

In my dissertation work, I applied both types of models to answer questions in neurobiology. Molecular dynamics was applied to probe the gorge fluctuation behavior of acetylcholinesterase; finite element simulations were used to connect synaptic geometry with electrophysiological response.

The synapse is the point of communication where a neuron sends its signal to another cell. The geometries of the synaptic cleft, bounded by pre- and postsynaptic membranes, differ by muscle type. Synaptic signal can be carried by the neurotransmitter acetylcholine (ACh), which is released by the neuron upon arrival of an action potential. ACh diffuses across the cleft, binds to and activates the postsynaptic receptors, generating a response in the receiving cell. The enzyme acetylcholinesterase (AChE) quickly degrades ACh to acetate and choline, deactivating the receptor and tapering off the response.

The enzyme AChE has several intriguing qualities. First, its key responsibility of regulating synaptic transmission has made it target of several chemical agents: from the drugs countering Alzheimer’s disease and myasthenia gravis (serious muscle weakness), to snake toxins and chemical weapons (such as sarin and VX). Second, the active site of AChE is buried 2 nm deep in the center of the enzyme, and connected to the protein surface by a narrow “gorge”. This design is counterintuitive considering the rapid catalysis of AChE; however, it has been suggested that selective control of substrate entry may be facilitated by a dynamical, fluctuating gorge.

We have performed two molecular dynamics simulations, each amounting to several nanoseconds: one of AChE by itself (10 ns), the other of AChE with a snake toxin, fasciculin (5 ns). From the static crystallographic structure, we see that fasciculin obstructs the entrance to the gorge, but it does not reach down the gorge.

Mechanisms of AChE inhibition by fasciculin. Measuring the width (“proper radius”) of the gorge every picosecond in the simulations, we can make a histogram of its distribution (Figure 1). Strikingly, this is not simply a symmetric, Gaussian distribution; there are two substates, one wider and one narrower. In addition, fasciculin shifts the whole distribution towards lower width values, and favors the narrower substate. These observations lead us to suggest that fasciculin restricts AChE gorge fluctuation in a dynamical fashion.

Looking at the average structures from the two simulation, we also noticed that the active site of AChE was changed: the histidine residue that served as the bridge in the proton-transfer pathway in catalysis has been oriented away from its normal position. As fasciculin did not reach down to the active site, this disruption of active site could only happen by allosteric means.

In sum, fasciculin inhibits AChE by three mechanisms: (i) steric obstruction of the entrance of the gorge; (ii) dynamic restriction of gorge width; (iii) allosteric disruption of the active site conformation. The first is a direct observation from the static crystallographic structure; the latter two are observations from our simulations.

Figure 1
: Distribution of the gorge proper radius. Solid line, from the simulation of AChE by itself; dashed line, from that of AChE with fasciculin.

“Porcupine plots”: visualizing concerted motions in AChE gorge fluctuation. What controls the fluctuation of the AChE gorge? Is it merely the movements of a few residues around the gorge bottleneck, or are there more global motions at work? With the large amount of data from the simulations, it is hard to determine one way or the other. We have created a simple device –the porcupine plot– to help us understand the correlation of motion in different parts of the protein with a functionally important motion, the gorge width in this case.

By plotting the correlation vector between the movement of each a-carbon atom and the gorge width, we see the likelihood and direction of concerted motions of different parts of the protein whenever the gorge becomes open. We are looking down the gorge in both panels of Figure 2.

Figure 2
: Porcupine plots. Left, from the simulation of AChE by itself; right, from that of AChE with fasciculin. The color of each vector corresponds to the magnitude thereof.

In the left panel, we see that the gorge opening does not only involve the residues near the gorge, but even residues some distance from the gorge also move concertedly to make way for the gorge to open. With fasciculin bound (right panel), much of this coordination has been suppressed; this may be one of the mechanisms by which fasciculin restricts the opening of the gorge. The simple device of porcupine plot has proven to be useful in visualising the concerted motions in proteins.

These nanosecond-scale simulations have enabled us to make comparisons with experiments. Fluorescence anisotropy decay experiment, a method detecting fast motions in proteins, has the resolution of nanoseconds. In cooperation with the Taylor laboratory, we have verified our simulation results by comparing the decay of anisotropy due to protein segmental motions calculated from simulation and that observed from experiment.

Going further upward to the organellar scale, we built a robust finite element software package to solve the time-dependent diffusion equation, and applied it to the diffusion of the neurotransmitter ACh across the synaptic cleft. Starting with the geometric shapes of the clefts as observed from electron microscopy, we calculated the postsynaptic responses using this package. The simulated response curves were then compared with electrophysiological data. We reproduced the different response trends in fast-twitch and slow-twitch muscle synapses.

I have learned this in my doctoral training: We can deepen our understanding of biomolecular behaviors by applying a combination of physical theory, computer technology, creative ways of analysis, and careful comparison with experiments. Computer simulation has opened up exciting ways of investigating the chemistry in biological systems.

> Kaihsu 's page, including access to full text thesis: <http://sansom.biop.ox.ac.uk/kaihsu/>

> Back to Prize index page

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