title: Efficient algorithms to explore conformation spaces of flexible protein loops.
abstract: 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.
authors.affiliation: Computer Science Department, Stanford University, S240 Clark Center, 318 Campus Drive, Stanford, CA 94305, USA. peggyyao@stanford.edu
authors.forename: Peggy
authors.initials: P
authors.lastname: Yao
authors.forename: Ankur
authors.initials: A
authors.lastname: Dhanik
authors.forename: Nathan
authors.initials: N
authors.lastname: Marz
authors.forename: Ryan
authors.initials: R
authors.lastname: Propper
authors.forename: Charles
authors.initials: C
authors.lastname: Kou
authors.forename: Guanfeng
authors.initials: G
authors.lastname: Liu
authors.forename: Henry
authors.initials: H
authors.lastname: van den Bedem
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Latombe
authors.forename: Inbal
authors.initials: I
authors.lastname: Halperin-Landsberg
authors.forename: Russ Biagio
authors.initials: RB
authors.lastname: Altman
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D011506:Proteins