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Efficient Algorithms to Explore Conformation Spaces of Flexible Protein Loops
October-December 2008 (vol. 5 no. 4)
pp. 534-545
Peggy Yao, Stanford University, Stanford
Ankur Dhanik, Stanford University, Stanford
Nathan Marz, Stanford University, Stanford
Ryan Propper, Stanford University, Stanford
Charles Kou, Stanford University, Stanford
Guanfeng Liu, Stanford University, Stanford
Henry van den Bedem, SLAC, Menlo Park
Jean-Claude Latombe, Stanford University, Stanford
Inbal Halperin-Landsberg, Stanford University, Stanford
Russ B. Altman, Stanford University, Stanford
Several applications in biology - e.g., incorporation of protein flexibility in ligand docking algorithms, interpretation of fuzzy X-ray crystallographic data, and homology modeling - require computing the internal parameters of a flexible fragment (usually, a loop) of a protein in order to connect its termini to the rest of the protein without causing any steric clash. One must often sample many such conformations in order to explore and adequately represent the conformational range of the studied loop. While sampling must be fast, it is made difficult by the fact that two conflicting constraints - kinematic closure and clash avoidance - must be satisfied concurrently. This paper describes two efficient and complementary sampling algorithms to explore the space of closed clash-free conformations of a flexible protein loop. The "seed sampling" algorithm samples broadly from this space, while the "deformation sampling" algorithm uses seed conformations as starting points to explore the conformation space around them at a finer grain. Computational results are presented for various loops ranging from 5 to 25 residues. More specific results also show that the combination of the sampling algorithms with a functional site prediction software (FEATURE) makes it possible to compute and recognize calcium-binding loop conformations. The sampling algorithms are implemented in a toolkit (LoopTK), which is available at https://simtk.org/home/looptk.

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Index Terms:
Biology and genetics, Robotics
Citation:
Peggy Yao, Ankur Dhanik, Nathan Marz, Ryan Propper, Charles Kou, Guanfeng Liu, Henry van den Bedem, Jean-Claude Latombe, Inbal Halperin-Landsberg, Russ B. Altman, "Efficient Algorithms to Explore Conformation Spaces of Flexible Protein Loops," IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol. 5, no. 4, pp. 534-545, Oct.-Dec. 2008, doi:10.1109/TCBB.2008.96
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