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Institute for Advanced Simulation (IAS)

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Seminar by Dr. Anne-Elisabeth Molza

IBPC, CNRS, Paris (France)

begin
21 Jun 2017 11:00
end
21 Jun 2017 12:00
venue
Lecture room 2009, Jülich GRS building (16.15)

In silico study of Ryanodine receptors

The Ryanodine Receptors (RyR) are members of the six-transmembrane ion channel superfamily. The RyRs are the biggest known ion channels with molecular mass over 2.3 MDa. The RyR are homotetrameric intracellular calcium channels and each subunit contains more than 5000 residues. Three mammalian isoforms exist, RyR1 located in the skeletal muscle, RyR2 in cardiac muscle and RyR3 located in the brain. All RyR share a similar three-dimensional organization with 80% of them folded into cytoplasmic assembly and 20% forming the transmembrane domain (TMD). Mutations of the RyR gene are associated with central core disease and malignant hyperthermia.

Here, we are studying the predominant isoform in skeletal muscle: RyR1. It plays an important role in sarcoplasmic reticulum calcium release, which is essential for excitation-contraction coupling.

RyR1 contains several binding sites for the channel activators: Ca2+, ATP, Caffeine and an antagonist: Ryanodine. Recently several cryo-electron microscopy studies have described the organization of closed and open states of RyR1, with high resolution up to 3.6A, paving the way to build three-dimensional structures by a fitting process. These structures contain several gaps and moreover they bear many uncertainties when it comes to the coordinates of certain residues or subdomains. However, knowledge about the opening / closing channel mechanism remains limited.

Given the lack of data, we decided to investigate the RyR combining in silico methods and experimental data when available. Our protocol uses an ab initio modeling method to fill the gaps and visual verifying to improve coordinates of “unknown” residues. The molecular dynamics flexible fitting method has been used to obtain an initial structure based on electron density for each condition and conformation. Thanks to coarse-grained approaches complemented by atomistic molecular modeling we are studying the TMD to provide new insights on the effect of different ligands on the channel's conformation. Nevertheless, between the cytoplasmic domain and the TMD, a large disordered region of 286aa exists. Because no structural information is currently available, we are going to study it using a flexible and interactive molecular dynamics (BioSpring) to improve auxiliary transmembrane helix presence and other transitory motions.


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