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shiva amiri professor mark s p sansom june 11 2004 n.
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Bioinformatics and molecular modeling studies of membrane proteins PowerPoint Presentation
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Bioinformatics and molecular modeling studies of membrane proteins

Bioinformatics and molecular modeling studies of membrane proteins

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Bioinformatics and molecular modeling studies of membrane proteins

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  1. Shiva Amiri Professor Mark S.P. Sansom June 11, 2004 Bioinformatics and molecular modeling studies of membrane proteins

  2. Membrane proteins sdf • constitute approximately 25% of the genome • important drug targets - nerve and muscle excitation - hormonal secretion - sensory transduction - control of salt and water balance etc. • malfunctions result in various diseases • difficult to get their structures Ligand gated ion channels (LGICs) • function is dependent upon the binding of a ligand. • examples of LGICs: nAChR, GABAA and GABAC receptors, 5HT3 receptor, Glycine receptor Sperelakis, N., Cell Physiology Source Book

  3. My project • to take available structural data and put the pieces together • main focus so far: using available information to predict the structure and motions of the α-7 nicotinic acetylcholine receptor (nAChR) we have: 4Å cryo-EM structure of AChR transmembrane domain 2.7Å crystal structure of ligand binding domain homolog task: to combine the separate domains • the use of bioinformatics and simulation tools to study functionally relevant motions of LGICs TM LB LB M3 M2 M4 M1 TM

  4. The process … homology modelling -Modeller, Procheck {θmax, zmax} 2 PDBs ZAlign termini distances bad contacts ( Unwin distances ) analysis – xfarbe plots make model using chosen {θ, z} GROMACS energy minimization procheck motion analysis: GNM CONCOORD electrostatics (Kaihsu Tai) pore dimensions - HOLE homology models of other LGICs

  5. Course grain methods of motion analysis • Gaussian network model (GNM) • a course-grained model to approximate fluctuations of residues • information on the flexibility and function of the protein • produces theoretical B-values • CONCOORD • LB region spikes rotating to one side and the TM spikes rotating in the opposite direction, suggesting a twisting motion of the receptor

  6. Summary Future work • modeling methods for LGICs • predicted structure of α-7 nAChR • used various methods (GNM, CONCOORD) to look at motions of the predicted structure of α-7 nAChR • models of anionic LGICs (GABA and glycine) using current α-7 nAChR structure • models of other LGICs • motion analysis of other LGICs • looking at the hydrophobic girdle (M2) of LGICs to study patterns of conservation and the behaviour of these residues during gating • simulation studies of constructed models