2010 | OriginalPaper | Chapter
Modeling Structural Heterogeneity in Proteins from X-Ray Data
Authors : Ankur Dhanik, Henry van den Bedem, Ashley Deacon, Jean Claude Latombe
Published in: Algorithmic Foundation of Robotics VIII
Publisher: Springer Berlin Heidelberg
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In a crystallographic experiment, a protein is precipitated to obtain a crystalline sample (crystal) containing many copies of the molecule. An electron density map (
edm
) is calculated from diffraction images obtained from focusing X-rays through the sample at different angles. This involves iterative phase determination and density calculation. The protein conformation is modeled by placing the atoms in 3-D space to best match the electron density. In practice, the copies of a protein in a crystal are not exactly in the same conformation. Consequently the obtained
edm
, which corresponds to the cumulative distribution of atomic positions over all conformations, is blurred. Existing modeling methods compute an “average” protein conformation by maximizing its fit with the
edm
and explain structural heterogeneity in the crystal with a harmonic distribution of the position of each atom. However, proteins undergo coordinated conformational variations leading to substantial correlated changes in atomic positions. These variations are biologically important. This paper presents a sample-select approach to model structural heterogeneity by computing an ensemble of conformations (along with occupancies) that, collectively, provide a near-optimal explanation of the
edm
. The focus is on deformable protein fragments, mainly loops and side-chains. Tests were successfully conducted on simulated and experimental
edm
s.