Medical and Life Sciences
Computational modeling of protein switches
The Src-family kinases and their close relatives, such as Abl, function as molecular switches and are important targets for therapeutic intervention; for example, the c-Abl inhibitor Gleevec is used to treat chronic myolegenous leukemia. The development of specific inhibitors is complicated by the fact that human cells contain ~500 different protein kinases, all of which catalyze the same chemical reaction and contain highly conserved active sites. Because crystal structures provide only static views of certain states of each kinase, Nagar et al. used molecular dynamics simulations to help understand specific switching mechanisms. The simulations confirmed that the regulatory mechanism of the proto-oncogenic Abl protein shares an important feature with the regulatory mechanism of the related Src-family tyrosine kinases (Figure 10). This result was verified by in vitro experiments.
B. Nagar, O. Hantschel, M. A. Young, K. Scheffzek, D. Veach, W. Bornmann, B. Clarkson, G. Superti-Furga, and J. Kuriyan, “Structural basis for the autoinhibition of c-Abl tyrosine kinase,” Cell 112, 859 (2003). BER, HFSP, EMBL, EMBO, AF, GNMF, CAG, DRCRF, BWF
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Figure 10 |
The impact of carcinogens on DNA structure
Understanding the 3D structure of DNA that has been modified by chemical carcinogens is important in understanding the molecular basis of cancer and chemical toxicology. Peterson et al. studied [POB]dG, which is produced from metabolically activated tobacco-specific nitrosomines. This compound modifies the base guanine, posing a significant cancer risk. The results of nuclear magnetic resonance spectra for [POB]dG were used as inputs to the DUPLEX code, which produced a minimum energy structure that agreed with the NMR data.
L. A. Peterson, C. Vu, B. E. Hingerty, S. Broyde, and M. Cosman, “Solution structure of an O6-[4-oxo-4-(3-Pyridyl)butyl]guanine adduct in an 11mer DNA duplex: Evidence for formation of a base triplex,” Biochemistry ASAP, DOI: 10.1021/bi035217v (2003). BER, NIH, ORNL
Modeling enzyme structure and kinetics
Although information on the function of enzymes has been obtained experimentally,
there is still an essential missing link between the structures and biomolecular
dynamics and function. Yang et al. studied the binding change mechanism of
F1-ATPase, the enzyme responsible for most of the ATP synthesis in living
systems. By computing the chemical potential, they identified 
TP
as the tight binding site for ATP and DP
as the loose site. The half closed site was identified as the binding site
for the solution ADP and Pi in ATP synthesis; it is different from the empty
binding site for ATP hydrolysis. Based on this result, a consistent structural
and kinetic model for the binding change mechanism is being developed for
F1-ATPase.
W. Yang, Y. Q. Gao, Q. Cui, J. P. Ma, and M. Karplus, “The missing link between thermodynamics and structure in F1-ATPase,” PNAS 100, 874 (2003). BER, NIH
Interactions between amino acids and nucleobases
There is a paucity of theoretical information about interactions between amino acids and nucleobases. Dabkowska et al. made electronic-structure calculations concerning the simplest amino acid-nucleobase complex, i.e., the dimer of glycine and uracil. Glycine is the smallest amino acid, and uracil is a building pyrimidine nucleobase of RNA. They demonstrated that the most stable complexes between uracil and glycine are formed when the carboxylic group of glycine is bound through two hydrogen bonds to uracil.
I. Dabkowska, J. Rak, and M. Gutowski, “Computational study of hydrogen-bonded complexes between the most stable tautomers of glycine and uracil,” J. Phys. Chem. A 106, 7423 (2002). BER, KBN