Cartoon modeling of proteins.pptVIP

Cartoon modeling of proteins Fred Howell and Dan Mossop ANC Informatics Overview Why / how to model intracellular processes? Examples: MCell, Stochsim, Virtual Cell Cartoon models Wheres the data on structure / interactions? A new 3D protein interaction simulator post synaptic density self-assembly vesicle formation vesicle transport Futures speculations Why / how to model intracellular processes? Ordered soup of ~1,000,000 different types of macromolecules Complex and specific network of interactions Ion channels and complexes the tip of the iceberg (croutons?) Much work on gene networks / intracellular pathways Mostly ignores spatial effects (well mixed pool / kinetics) Hypothesis of mechanisms typically involve cartoon descriptions / precise shapes / jigsaw-like interactions of proteins Computer models typically dont Intracellular pathway modeling Single mixed pool: Rate equations / kinetics (as differential equations) Stochastic simulators (Stochsim) A number of connected compartments Virtual cell Individual molecules / brownian motion MCell ... but none of them take into account the actual shapes of proteins! Single protein modeling The great protein folding problem - what shapes can the sequence form? Uses molecular dynamics (motion of each atom in the molecule) to try and predict low energy folding conformations of primary sequence hard, not there yet Intermediate protein modeling - recognise characteristic subsequences of amino acids, guess substructures like alpha helices, beta sheets promising, not there yet Timescales of femto- and pico- seconds ... data available from crystallography on some proteins (PDB) ... predicting binding sites is very hard Cartoon models Typically used to hypothesise mechanisms Getting data on protein shapes PDB: coordinates of each atom in protein One possibility: cluster analysis to reduce to a number of subunits Getting data on protein interactions This is harder Ideally would like binding sites, bond angles,