title: Mapping allostery through computational glycine scanning and correlation analysis of residue-residue contacts.
abstract: Understanding allosteric mechanisms is essential for the physical control of molecular switches and downstream cellular responses. However, it is difficult to decode essential allosteric motions in a high-throughput scheme. A general two-pronged approach to performing automatic data reduction of simulation trajectories is presented here. The first step involves coarse-graining and identifying the most dynamic residue-residue contacts. The second step is performing principal component analysis of these contacts and extracting the large-scale collective motions expressed via these residue-residue contacts. We demonstrated the method using a protein complex of nuclear receptors. Using atomistic modeling and simulation, we examined the protein complex and a set of 18 glycine point mutations of residues that constitute the binding pocket of the ligand effector. The important motions that are responsible for the allostery are reported. In contrast to conventional induced-fit and lock-and-key binding mechanisms, a novel "frustrated-fit" binding mechanism of RXR for allosteric control was revealed.
authors: UT-ORNL Graduate School of Genome Science and Technology , Knoxville, Tennessee 37996, United States.
authors: Quentin R
authors: QR
authors: Johnson
authors: Richard J
authors: RJ
authors: Lindsay
authors: Ricky B
authors: RB
authors: Nellas
authors: Elias J
authors: EJ
authors: Fernandez
authors: Tongye
authors: T
authors: Shen
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002645:Chickens; D005998:Glycine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D025341:Principal Component Analysis; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D005998:Glycine