title: Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion.
abstract: A variety of experimental evidence suggests that rapid, long-range propagation of conformational changes through the core of proteins plays a vital role in allosteric communication. Here, we describe a non-equilibrium molecular dynamics simulation method, anisotropic thermal diffusion (ATD), which allowed us to observe a dominant intramolecular signaling pathway in PSD-95, a member of the PDZ domain protein family. The observed pathway is in good accordance with a pathway previously inferred using a multiple sequence analysis of 276 PDZ domain proteins. In comparison with conventional solution molecular dynamics methods, the ATD method provides greatly enhanced signal-to-noise, allowing long-distance correlations to be observed clearly. The ATD method requires neither a large number of homologous proteins, nor extremely long simulation times to obtain a complete signaling pathway within a protein. Therefore, the ATD method should prove to be a powerful and general complement to experimental efforts to understand the physical basis of intramolecular signaling.
authors: Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-2240, USA.
authors: Nobuyuki
authors: N
authors: Ota
authors: David A
authors: DA
authors: Agard
mesh_terms: D000495:Allosteric Site; D000818:Animals; D016880:Anisotropy; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D004058:Diffusion; D000076122:Disks Large Homolog 4 Protein; D006358:Hot Temperature; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008565:Membrane Proteins; D008958:Models, Molecular; D015233:Models, Statistical; D009419:Nerve Tissue Proteins / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D012984:Software; D013696:Temperature; D013997:Time Factors
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C033652:postsynaptic density proteins