title: Computational approaches to detect allosteric pathways in transmembrane molecular machines.
abstract: Many of the functions of transmembrane proteins involved in signal processing and transduction across the cell membrane are determined by allosteric couplings that propagate the functional effects well beyond the original site of activation. Data gathered from breakthroughs in biochemistry, crystallography, and single molecule fluorescence have established a rich basis of information for the study of molecular mechanisms in the allosteric couplings of such transmembrane proteins. The mechanistic details of these couplings, many of which have therapeutic implications, however, have only become accessible in synergy with molecular modeling and simulations. Here, we review some recent computational approaches that analyze allosteric coupling networks (ACNs) in transmembrane proteins, and in particular the recently developed Protein Interaction Analyzer (PIA) designed to study ACNs in the structural ensembles sampled by molecular dynamics simulations. The power of these computational approaches in interrogating the functional mechanisms of transmembrane proteins is illustrated with selected examples of recent experimental and computational studies pursued synergistically in the investigation of secondary active transporters and GPCRs. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.
authors.affiliation: Computational Molecular Biology Group, Institute for Mathematics, Arnimallee 6, 14195, Berlin, Germany; Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065, USA; Department of Physics, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stolzenberg
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: LeVine
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065, USA; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: lei.shi2@nih.gov.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D008051:Lipid Bilayers / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins
keywords: Allosteric interaction network; Molecular dynamics; Transmembrane protein