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TEMA FRIDMAN |
Simulating DNA Conformational Change |
In Dr. Olsonís laboratory, I have been developing
a novel computational approach for investigating the conformational space
of DNA. We are working in collaboration with Dr. Andrey A. Gorin, from the
Dinshaw Patel laboratory at the Memorial Sloan-Kettering Cancer Center,
on methods to simulate the B to A transition in two homogeneous oligonucletide
duplexes, d(A6*'T6) and d(G6*C6), with very different experimental properties.
The GC-rich sequence, which readily undergoes this large-scale transformation
in solutions of low water content, is said to be ìA-philic,î while the
AT-containing sequence, which resists conformational conversion under the
same conditions, is termed ìA-phobicî [1]. Our work to date has focused
on appropriate methods to simulate large-scale changes of double helical
conformation. The problem is complicated by the known conformational variability
of the DNA chain and the constraints of hydrogen bonding between bases
on complementary DNA strands. |
A distribution function of the density of configuration states in S1ide-Twist-Roll
space is constructed that serves two purposes: to visualize the simulated
states and to ensure progress toward reaching the equilibrium [2]. For
processes like the B to A transitions, it is very important to know not
only the global minimum, but also the complete landscape of the potential
energy, including other potential conformational states. The latter high
energy states may be stabilized by changes in the local chemical environment, e.g., ions, proteins, etc. |
Simulations to date with standard aII-atom potential functions [3,4]
and an assumed dielectric constant of 4 show significant sequence-dependent
differences in conformational behavior. The d(G6*C6) chain adopts two distinct
conformational states that correspond to A and B double helical forms with
higher preference given to the B form. The d(A6-T6) molecule does not
occupy the region associated with the A-form. Other experimentally known
features, such as the correlation between Slide and Twist, are reproduced. |
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