1998 Annual Report
Grand Challenge Projects
Protein Dynamics and BiocatalysisP. A. Bash, Northwestern
University Medical School | |
Research Objectives
A guiding principle
of molecular biology is that the structure of a biomolecule defines
its function. This principle is especially true in the case of
the protein molecules known as enzymes, which serve as highly
specific and extraordinarily efficient catalysts of biochemical
reactions. Despite the growing availability of the atomic structures
of enzymes, details of the chemical mechanisms employed by enzymes
to achieve their catalytic prowess remain elusive.
The goal of this project
is to develop a greater understanding of the mechanisms involved
in enzyme catalysis. We are studying two different enzymes, one
a protein, the other a nucleic acid. The protein enzyme that we
are investigating is beta-lactamase, which is responsible for
the efficient hydrolysis of antibiotic agents such as penicillin
and cephalosporin. The nucleic acid enzyme we are investigating
is the hammerhead ribozyme, which is a self-cleaving ribozyme
suggested as a model for the primordial enzyme before proteins
came into existence.
Computational Approach
The methods we use
are based on the physical and chemical principles of statistical
mechanics and quantum mechanics, and they are implemented in computational
form using techniques from computational chemistry. To carry out
our calculations, we used both the T3E and the J90 machines at
NERSC. The molecular dynamics and quantum mechanical calculations
were done on the T3E and J90 machines, respectively. Accomplishments
We have developed a
model of the Michaelis complex for the TEM-1/penicillin system
from molecular dynamics simulations (see figure). We have also
developed a model quantum and molecular mechanics (QM/MM) Hamiltonian
for the beta-lactamase system, calibrating the Hamiltonian parameters
against high levelab initiocalculations.
The catalytic mechanism
of the hammerhead ribozyme is being investigated using a number
of techniques that have been developed in our laboratories. An
important goal is to determine the conformational flexibility
of the active site of the ribozyme and the role that this may
play in the catalytic mechanism. The new nucleic acid molecular
mechanics force field in the CHARMM program will help us perform
a classical molecular dynamics study of the hammerhead ribozyme.
SignificanceThe dynamic properties of proteins and nucleic acids are difficult to investigate experimentally, but they are essential for an understanding of their function. Computer simulations can provide the necessary insights, at an atomic level of detail, for a complete understanding of the relationship between biomolecular dynamics/structure and function. |
For example,
while the class of enzymes known as beta-lactamases are largely
responsible for the increasing resistance of bacteria to antibiotics,
the precise chemical resistance mechanism used by this enzyme
is still unknown. Simulations are critical for further study of
this mechanism.
Similarly, RNA was recently discovered to catalyze
its own cleavage or that of other RNA molecules. The dual capacity
of RNA to act as an information transfer molecule and an enzyme
has led to speculation on the role of RNA in primordial life.
Simulations involving the hammerhead ribozyme, the smallest of
the catalytic RNAs, will be very useful in further investigations
of RNA. Publications
M. A. Cunningham and
P. A. Bash, "Systematic procedure for the development of
accurate QM/MM model Hamiltonians," inComputer Simulations
in Biomolecular Systems, edited by W. F. Van Gunsteren, P.
K. Weiner, and A. J. Wilkinson (Kluwer, Dordrecht, Neth., 1997),
pp. 177-95.
M. A. Cunningham, R.
E. Gillilan, and P. A. Bash, "Computational enzymology,"
Can. Chem. News 49, 9 (1997).
M. A. Cunningham and
P. A. Bash, "Computational enzymology," Biochimie. 79,
687-9 (1997).
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