title: Microscopic Characterization of Membrane Transporter Function by In Silico Modeling and Simulation.
abstract: Membrane transporters mediate one of the most fundamental processes in biology. They are the main gatekeepers controlling active traffic of materials in a highly selective and regulated manner between different cellular compartments demarcated by biological membranes. At the heart of the mechanism of membrane transporters lie protein conformational changes of diverse forms and magnitudes, which closely mediate critical aspects of the transport process, most importantly the coordinated motions of remotely located gating elements and their tight coupling to chemical processes such as binding, unbinding and translocation of transported substrate and cotransported ions, ATP binding and hydrolysis, and other molecular events fueling uphill transport of the cargo. An increasing number of functional studies have established the active participation of lipids and other components of biological membranes in the function of transporters and other membrane proteins, often acting as major signaling and regulating elements. Understanding the mechanistic details of these molecular processes require methods that offer high spatial and temporal resolutions. Computational modeling and simulations technologies empowered by advanced sampling and free energy calculations have reached a sufficiently mature state to become an indispensable component of mechanistic studies of membrane transporters in their natural environment of the membrane. In this article, we provide an overview of a number of major computational protocols and techniques commonly used in membrane transporter modeling and simulation studies. The article also includes practical hints on effective use of these methods, critical perspectives on their strengths and weak points, and examples of their successful applications to membrane transporters, selected from the research performed in our own laboratory.
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: J V
authors: JV
authors: Vermaas
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: N
authors: N
authors: Trebesch
authors: University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: C G
authors: CG
authors: Mayne
authors: University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: S
authors: S
authors: Thangapandian
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: M
authors: M
authors: Shekhar
authors: University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: P
authors: P
authors: Mahinthichaichan
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: J L
authors: JL
authors: Baylon
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: T
authors: T
authors: Jiang
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: Y
authors: Y
authors: Wang
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: M P
authors: MP
authors: Muller
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: E
authors: E
authors: Shinn
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: Z
authors: Z
authors: Zhao
authors: University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
authors: P-C
authors: PC
authors: Wen
authors: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois at Urbana-Champaign, Urbana, IL, United States; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States. Electronic address: emad@life.illinois.edu.
authors: E
authors: E
authors: Tajkhorshid
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D001665:Binding Sites; D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055672:Static Electricity; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C488962:GlpT protein, E coli; D008051:Lipid Bilayers; D026901:Membrane Transport Proteins
keywords: Active transport; Biological systems modeling; Conformational change; Free energy calculations; Lipid bilayers; Membrane transporter; Molecular dynamics