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Mini-workshop on Mathematical Modeling and Computer Simulation for Transmembrane Proteins: Focusing on Ion Channels and Transporters

May 18, 2018

B07, Science College, Department of Applied Mathematics, Feng Chia University

Invited Speakers:
Ren-Shiang Chen (Tunghai University)
Simone Furini (University of Siena)
Tzyy-Leng Horng (Feng Chia University)
Nien-Jen Hu (National Chung Hsing University)
Tai-Chia Lin (National Taiwan University)

Tzyy-Leng Horng (Feng Chia University)
Tai-Chia Lin (National Taiwan University)

Aim & Scope:

Transmembrane proteins span the entire width of the lipid bilayer. They have hydrophobic regions containing a high fraction of non-polar amino acids and hydrophilic regions containing a high fraction of polar amino acids. Certain hydrophobic regions organize themselves inside the bilayer as transmembrane α-helices while more hydrophilic regions are in contact with the aqueous intracellular and extracellular environments. Interaction energies are very high between hydrophobic regions of the protein and hydrophobic regions of the lipid bilayer, as well as between hydrophilic regions of the protein and the extracellular and intracellular environments. These interactions strongly stabilize transmembrane proteins within the bilayer, thus preventing their extracellular and cytoplasmic regions from flipping back and forth. Ion channels have a three-dimensional structure that delimits an aqueous pore through which certain ions can pass. They provide the ions with a passage through the membrane.
Each channel may be regarded as an excitable molecule as it is specifically responsive to a stimulus and can be in at least two different states: closed and open. Channel opening, the switch from the closed to the open state, is tightly controlled by: (1) a change in the membrane potential – these are voltage-gated channels; (2) the binding of an extracellular ligand, such as a neurotransmitter – these are ligand-gated channels, also called receptor channels or ionotropic receptors; (3) the binding of an intracellular ligand such as Ca 2+  ions or a cyclic nucleotide; (4) mechanical stimuli such as stretch – these are mechanoreceptors. The channel’s response to its specific stimuli, called gating, is a simple opening or closing of the pore. The pore has the important property of selective permeability, allowing some restricted class of small ions to flow passively down their electrochemical gradients. These gated ion fluxes through pores make signals for the nervous system. Transporters are specialized membrane-spanning proteins that assist in the movement of ions, peptides, small molecules, lipids and macromolecules across a biological membrane. There are two different types of transport; passive and active. Passive transport requires no energy input as transport follows a concentration gradient. In contrast active transport requires energy (usually from ATP hydrolysis) to transport substances into a cell against the concentration gradient. Membrane transporters can be also divided into three main classes; ABC transporters, P-type ATPases and the solute carrier family (SLC). ABC transporters are primary active transporters, which transport a wide range of substrates mainly to the outside of a cell membrane or organelle. Their substrates include: lipids and sterols, ions and small molecules, drugs and large polypeptides. ABC transporters play a critical role in the development of multi-drug resistance in cancer cells. Overexpression of ABC transporters can result in chemotherapeutics being pumped out of cell faster than they can enter. P-type ATPases are a family of transport enzymes which pump cations across the membrane using primary active transport. Examples of this family include Ca 2+ - ATPases and Na + ,K + -ATPases. The solute carrier family includes transporters that function by secondary active transport and facilitative diffusion. They are located on the cell membrane as well as on the intracellular membrane of organelles. Examples of the solute carrier family include the biogenic amine transporters (NET, DAT and SERT) and the Na + /H +  exchanger. Inhibitors of the SLC family of transporters have proved useful in the treatment of a variety of disorders, including depression (SERT), epilepsy (GABA
transporter) and Parkinson's disease (DAT). Mathematical modeling and computer simulations of ion channels and transporters has been an intensive research subject in mathematical physiology. There are two popular mathematical models for this subject: (1) continuum models like Poisson-Boltzmann (PB) and Poisson-Nernst- Planck (PNP) equations; (2) particle models like molecular dynamics (MD) and Brownian dynamics (BD). Continuum model has the advantage of better computational efficiency but disadvantage of neglecting many atomistic details of protein, while particle model considers atomistic details of protein but suffers poor computational efficiency. Invited speakers of this workshop includes an expert in MD (Simone Furini), two experts in PB/PNP (Tzyy-Leng Horng and Tai-Chia Lin), two experimentalists in ion channel and transporter respectively (Ren-Shiang Chen and Nien-Jen Hu). We hope communications in this workshop will bring up an interdisciplinary collaboration with mathematical society on solving important problems in this field.

Contact: Peggy Lee, peggylee@ncts.tw, +886-2-3366-8815

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