title: Kinetic regulation of multi-ligand binding proteins.
abstract: BACKGROUND
  Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation.
  
  
  RESULTS
  In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated.
  
  
  CONCLUSIONS
  The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion.
authors.affiliation: Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008, Kazan, Russia.
authors.forename: Diana V
authors.initials: DV
authors.lastname: Salakhieva
authors.affiliation: Centre for Systems, Dynamics and Control, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Harrison Building, North Park Road, Exeter, EX4 4QF, UK.
authors.forename: Ildar I
authors.initials: II
authors.lastname: Sadreev
authors.affiliation: Department of Mechanical Engineering, The University of Hong Kong, Pokfulam Road, Hong Kong, China. mzqchen@gmail.com.
authors.forename: Michael Z Q
authors.initials: MZ
authors.lastname: Chen
authors.affiliation: Department of Dermatology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Umezawa
authors.affiliation: Biophysics & Bionics Lab, Institute of Physics, Kazan Federal University, Kazan, 420008, Russia.
authors.forename: Aleksandr I
authors.initials: AI
authors.lastname: Evstifeev
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Biophysics & Bionics Lab, Institute of Physics, Kazan Federal University, Kazan, 420008, Russia.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Kotov
mesh_terms: D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D008024:Ligands; D011506:Proteins; D002118:Calcium
keywords: Calcium; Calmodulin; Ligand-receptor binding; Transient kinetics