Structure Activity Relationships (SAR) of Membrane Bound Compounds and Complexes
June 21, Tue, 2005
10:00am - 11:00am, rm 2046, Haworth
Explicit and implicit Monte Carlo (MC) and molecular dynamics (MD) simulations have been employed to studying SAR of the main classes of the membrane active compounds: carriers, siderophores, channels, and cotransporters.
MC studies revealed external coordinated and water separated complexes of transmembrane carriers: cyclic peptide antibiotics, cryptands, and crown-ethers.
Free energies and transfer barriers of the antibiotic lasalocid A-amine complexes were calculated by the finite difference thermodynamic integration method. The values correlate well with the amine transportation rates: serotonin > dopamine > noradrenaline > adrenaline.
Anion, cation, and ion pair coordination in the water-filled pore of the amphotericin B-cholesterol complex was studied by explicit MD simulations. Multiple motifs of the coordination were found. The dual selectivity puzzle of the channel was solved.
Implicit MD simulations with Generalized Born solvation model have been employed to predict the structure of the double spanning transmembrane segments of several integral membrane proteins (cotransporters). The peptides folded into the functional hairpin structure of two antiparallel helices connected by a short structured loop. The simulations of the cysteine substituted and inhibitor-labeled segments revealed functionally important residues controlling the protein functions. Different types of the inhibitory mechanism have been described.