title: Elucidation of molecular kinetic schemes from macroscopic traces using system identification.
abstract: Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems.
authors.affiliation: Department of Neurology and Center for Translational Systems Biology, Icahn School Of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Miguel
authors.identifier: 0000-0003-1804-8136
authors.initials: M
authors.lastname: Fribourg
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Diomedes E
authors.identifier: 0000-0002-0384-073X
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
authors.affiliation: Department of Neurology and Center for Translational Systems Biology, Icahn School Of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
authors.affiliation: Department of Signals Systems and Radiocommunications, Universidad Politécnica de Madrid, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Galocha-Iragüen
authors.affiliation: Department of Electrical Engineering, Universidad de Oviedo, Gijón, Spain.
authors.forename: Fernando
authors.identifier: 0000-0001-7959-2114
authors.initials: F
authors.lastname: Las-Heras Andrés
authors.affiliation: Department of Neuroscience, Icahn School of Medicine, New York, New York, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brezina
mesh_terms: D000465:Algorithms; D001704:Biopolymers / Q000737:chemistry* / Q000378:metabolism*; D002468:Cell Physiological Phenomena; D003198:Computer Simulation; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D008956:Models, Chemical; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001704:Biopolymers