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Supercomputer Shows Role Of Dynamics When Enzymes Link To Substrates

Role of Molecular Dynamics in Enzyme Specificity is Quantified for the First Time

Published 08/03/1998

For more information, contact:
Philip Terranova, Drexel University
215-895-2613 (
Sheldon Smart, University of Houston
713-743-8190 (
Ann Redelfs, NPACI/SDSC
619-534-5032 (

DREXEL UNIVERSITY, PHILADELPHIA, PA; HONG KONG UNIVERSITY OF SCIENCE AND TECHNOLOGY, CHINA; UNIVERSITY OF HOUSTON, TX; AND UC SAN DIEGO, CA--It has long been known that molecular recognition between enzyme and substrate depends to a very large extent on the shape, or "conformation," of both molecules. The active site is a "pocket" in the larger enzyme, into which the smaller substrate fits, like a hand wriggling into a glove. Now a far-flung team of scientists has shown that shape isn't everything: the wriggling counts, too. With large-scale computer simulations run at the San Diego Supercomputer Center (SDSC), they've shown, quantitatively, how one of the fastest enzymes in the world does its work. Internet users can see an animation of the enzyme they studied at

The scientists are Huan-Xiang Zhou (Physics Department, Drexel University, and the Hong Kong University of Science and Technology), Stanislaw T. Wlodek (Texas Center for Advanced Molecular Computation, University of Houston), and J. Andrew McCammon (Joseph Mayer Professor of Theoretical Chemistry in the Department of Chemistry and Biochemistry and the Department of Pharmacology, University of California, San Diego). They used a combination of computational models and theoretical calculations to obtain their results, which are published in the August 4 issue of the Proceedings of the National Academy of Sciences.

The work was done in the Biomolecular Structure and Energetics Project, headed by McCammon, which is part of a major Molecular Science thrust within the National Partnership for Advanced Computational Infrastructure (NPACI), one of the two national high-performance computing partnerships funded by the National Science Foundation. SDSC is the leading-edge site of NPACI.

The team studied the enzyme acetylcholinesterase (AChE), which acts very quickly to control the communication among nerve and muscle cells. The speed of AChE has been puzzling, because its active site appears to be accessible only by a partly-blocked channel from the enzyme's surface. Earlier work by McCammon, Wlodek, and other collaborators showed that "breathing" motions in AChE open and close the channel enough to allow the substrate acetylcholine (ACh) to enter the active site. The new work shows that the detailed time course of the breathing motions allows ACh to bind almost as fast as if the channel were always open. Importantly, this work also shows that the motions discriminate against the binding of possible substrates that are larger than the natural substrate ACh. The result is a new concept, "dynamic selectivity," for the recognition of molecules in non-equilibrium systems such as living organisms.

"This is excellent and significant work," said Attila Szabo, a leading theoretician in the Laboratory of Chemical Physics at the National Institutes of Health. "The researchers have very nicely combined analytic theory and simulations to yield a physically interesting result."

Zhou, a theoretical biophysicist, performed an analysis of the statistics of a long simulation of AChE dynamics. He found that although the channel to the active site is open wide enough to admit the substrate ACh only 2.4 percent of the time, the breathing is rapid enough to assure that whenever there is substrate about, it will likely be able to slip through to the active site during one of the openings. Larger substrates require larger openings of the channel, which occur less frequently. Such substrates are therefore more likely to diffuse away from AChE before they can enter the active site and react. Zhou noted, "Much understanding has been achieved by computer simulation of molecules in fluctuation, but our new, quantitative understanding required an unusually long simulation to enable analysis of many, many fluctuations."

"Long" in this case means a nanosecond (one-billionth of a second), during which the simulation followed the atomic-level interactions and readjustments of AChE in femtosecond (quintillionth of a second) time steps. "That's how fast things operate on the molecular level," McCammon explains. He is the developer of many of the computer simulation methods that permit this close scrutiny of the dance of the molecules.

The nanosecond-long molecular dynamics simulation was performed by Houston's Wlodek. He began the work on an Intel Paragon machine at SDSC, using high-speed connections from Texas. The Paragon was then one of the world's largest machines, and a 5-picosecond chunk of the simulation took about 10 hours on 128 processors. Current simulations of AChE and other molecules make use of the SDSC Cray T3E and IBM SP machines.

"The computation could not have been done on lesser machines," Wlodek commented. The full system (AChE dimer plus surrounding water molecules) totals about 130,000 atoms. "The newer machines can work faster," he said, "but it's still a monster calculation."

Enzymes are the biological catalysts that facilitate chemical reactions in living systems. AChE is found in nerves and muscles and operates by rapidly binding to and hydrolyzing (breaking apart) ACh, which is a neurotransmitter. AChE is thus the essential "off switch" for signal transmission across nerve synapses. It has one of the highest catalytic efficiencies known, consistent with the need for speedy responses in the neuromuscular system.

But when the 3-D structure of the enzyme was determined in 1991, "it presented a puzzle," said McCammon. There was only one apparent route of access to the active site, a 20-angstrom deep gorge running into the interior of the molecule from the surface--a gorge that seemed too narrow to admit acetylcholine. "Yet the reaction occurs so rapidly that it appears to be limited only by diffusion--by how fast the substrate ACh could get to the AChE, just as if the active site were right on the surface," said McCammon. Early molecular dynamics simulations by McCammon and his group showed that the active site did seem to open wide enough to admit the substrate, and also that the electrostatic field of AChE played a role in guiding ACh to the active site.

"But now we have the first quantitative calculation of the role of molecular dynamics in the selectivity of an enzyme," McCammon says, "and all of this makes a good deal of evolutionary sense. We've learned that nerves and muscles evolved to be both fast and choosy, with the same reaction at the heart of it all."

The work was supported by the Research Grants Council of Hong Kong, the National Institutes of Health, the National Science Foundation, and the San Diego Supercomputer Center (SDSC). Drexel University provided start-up funding to Zhou.

Drexel University, founded in 1891, is a privately controlled, nonsectarian, coeducational center of higher learning serving 11,000 students. The University of Houston, a metropolitan research and teaching institution, serves more than 30,000 students and offers a full range of undergraduate, graduate, and professional degrees.

The San Diego Supercomputer Center is a research unit of the University of California, San Diego. SDSC is sponsored by the National Science Foundation through the National Partnership for Advanced Computational Infrastructure and by other federal agencies, the State and University of California, and private organizations. For additional information about NPACI or SDSC, see and, or contact Ann Redelfs at NPACI/SDSC, 619-534-5032,