COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 149
Clinical data taken from the published literature were used for the measured values of the kinetic
parameters. These values were then used in model simulations to determine whether a direct link could
be established between the SNP and the disease (anemia).
The computational modeling revealed two results. For the G6PD and PK variants analyzed, there
appeared to be no clear relationship between their kinetic properties as a function of sequence variation
or SNP. However, upon assessment of overall biological function, a correlation was found between the
sequence variation of G6PD and the severity of the clinical disease. Thus, in silico modeling of biological
processes may aid in analysis and prediction of SNPs and pathophysiological conditions.
5.4.2.4 Spatial Inhomogeneities in Cellular Development,
Simulation models can be used to provide insight into the significance of spatial inhomogeneities.
For example, the interior of living cells does not resemble at all a uniform aqueous solution of dissolved
chemicals, and yet this is the implicit assumption underlying many views of the cell. This assumption
serves traditional biochemistry and molecular biology reasonably well, but research increasingly dem-
onstrates that the physical locations of specific molecules are crucial. Multiprotein complexes act as
machines for internal movements or as integrated circuits in signaling. Messenger RNA molecules are
transported in a highly directed fashion to specific regions of the cell (in nerve axons, for example). Cells
adopt highly complex shapes and undergo complex movements thanks to the matrix of protein fila-
ments and associated proteins within their cytoplasm.
5.4.2.4.1 Unraveling the Physical Basis of Microtubule Structure and StabilityMicrotubules are cylin-
drical polymers found in every eukaryotic cell. Microtubles play a role in cellular architecture and as
molecular train tracks used to transport everything from chromosomes to drug molecules. An under-
standing of microtubule structure and function is key not just to unraveling fundamental mechanisms
of the cell, but also to opening the way to the discovery of new antiparasitic and anticancer drugs.
Until now, researchers have known that the microtubules, constructed of units called protofilaments
in a hollow, helical arrangement, are rigid but not static, and undergo periods of growth and sudden
collapse. Yet the mechanism for this construction-destruction had eluded researchers.
Over the past several years, McCammon and his colleagues have pioneered the use of a combina-
tion of an atomically detailed model for a microtubule and large-scale computations using the adaptive
Poisson-Boltzmann Solver to create a high-resolution, 1.25-million-atom map of the electrostatic inter-
actions within the microtubule.^61
More recently, David Sept and Nathan Baker of Washington University and McCammon used the
same technique to successfully predict the helicity of the tubule with a striking correspondence to
experimental observation.^62 Based on the lateral interactions between protofilaments, they determined
that the microtubule prefers to be in a configuration in which the protofilaments assemble with a seam
at each turn, rather than spiraling smoothly upward with alpha and beta monomers wrapping the
microtubule as if it were a barber’s pole. At the end of each turn, a chain of alphas is trailed by a chain
of betas, then after that turn, a chain of alphas, and so on. It is as if the red and white stripes on the
barber’s pole traded places with every twist (Figure 5.8).
(^61) N.A. Baker, D. Sept, S. Joseph, M.J. Holst, and J.A. McCammon, “Electrostatics of Nanosystems: Application to Microtubules
and the Ribosome,” Proceedings of the National Academy of Sciences 98(18):10037-10041, 2001.
(^62) D. Sept, N.A. Baker, and J.A. McCammon, “The Physical Basis of Microtubule Structure and Stability,” Protein Science
12(10):2257-2261, 2003.