DOC PREVIEW
CALTECH APH 161 - Lecture notes

This preview shows page 1-2-3-27-28-29 out of 29 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 29 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

The The ““Biology is too complicatedBiology is too complicated””Defense RejectedDefense Rejected“The obvious is that which is never seen until someone expressesit simply.” Christian MorgensternIon Channels: Models of GatingIon Channels: Models of GatingRob PhillipsCalifornia Institute of Technology(Perozo and Rees)(Gillespie and Walker)Life and the SensesLife and the SensesLiving organisms are full ofsensors, some of which we areconscious of, others of which weare not.Obvious examples – touch,hearing, vision, taste, smellLess obvious – sharks and theampullae of Lorenzini – electricaldetection.Sensors from pH to temperature tosugar.Reminder on Ion Distribution andReminder on Ion Distribution andTransport in CellsTransport in CellsCells divided into a number ofmembrane-bound compartments.Concentrations in differentcompartments can be orders ofmagnitude different.Proteins (ion channels, transporters)mediate these concentration gradients.Membrane proteins central to hugerange of processes – cell signaling,nerve impulses, nutrient transport, etc.Crossing the MembraneCrossing the MembraneIon Channels and TransientIon Channels and TransientPermeabilityPermeabilityChannels open inresponse to avariety of differentstimuli.Key mechanismsare voltage gating,ligand binding-induced gatingand mechanicaltension in themembrane.How We Know: Structural BiologyHow We Know: Structural BiologySome famous examples of ion channels studied by structuralbiologists.K ChannelNicotinic acetylcholinereceptor(Unwin et al.)(Doyle et al.)(Doyle et al.)EM & X Ray structuresSynchrotronHow We Know: Patch ClampingHow We Know: Patch ClampingpA currents lasting severalmilliseconds.The idea: grab a patch ofmembrane and apply apotential difference to measurethe currents.Fraction of time spent opendepends upon magnitude ofdriving force.(Sukharev et al.)Conductance of Conductance of MscL MscL Under TensionUnder TensionElectrophysiologymeasurements (patchclamping) lead to currentvs membrane tension.Measurements revealfive distinct conductancesubstates.(Sukharev et al.)Consequences of Ion Channel Gating:Consequences of Ion Channel Gating:The Action PotentialThe Action PotentialUbiquitous Phenomenon ofUbiquitous Phenomenon ofMechanosensationMechanosensation(Gillespie and Walker)Touch sensationin wormMechanicalresponse of haircellsThe main point:mechanosensationis everywhere.Informationalcurrency iselectrical –detection ismechanical.Repetition of samemotif – mechanicalexcitation resultsin transient flow ofions.Mechanosensitive Mechanosensitive Channels asChannels asOsmotic Pressure Relief ValvesOsmotic Pressure Relief Valves(Perozo and Rees)Hierarchy of mechanically-gatedchannels.Properties of channel have beeninvestigated using electrophysiology.Gating tension of MscL serves to avoidmembrane rupture.MscLMscKMscSMore on Osmotic ShockMore on Osmotic ShockCoarse-Grained Descriptions ofCoarse-Grained Descriptions ofMacromolecular StructureMacromolecular StructureDescription of biologicalstructures can be undertakenfrom a variety of differentperspectives.Two key ways of viewingstructure are ribbon diagramsand all-atom descriptions.Conformational Change DuringConformational Change DuringGatingGatingHypothesized structuralpathway for opening thechannel. Tilting of alphahelices and correspondingopening of the pore.Key Question: How doesmechanical tension couple tothe conformational change?What are the energeticconsequences to thesurrounding membrane as aresult of channel opening?(Sukharev et al.)Lipid Lipid BilayersBilayers (In Vitro) (In Vitro)Hydrophobic tails and polar headgroups.Favorable for lipids tospontaneously assemble to formbilayers.Molecular Continuum(Avanti Polar Lipids)Membranes In VivoReal biological membranes contain many different lipids &transmembrane proteins!Experimental Challenges forExperimental Challenges forModel: Lipid Tail LengthModel: Lipid Tail LengthGating tension depends upon the length ofthe lipid tails.(Avanti Polar Lipids)Free energy cost associated with mismatchbetween thickness of protein and lipids.(Perozo et al.)The Membrane Free EnergyThe Membrane Free EnergyThe idea: solve boundary problem for protein embedded inmembrane (Huang, Andersen and others).We use elasticity theory and can thereby compute the energy as afunction of protein shape.Bending:The Membrane Free Energy: PartThe Membrane Free Energy: Part22Tension (in plane Stretch):Stretch (out of plane):Protein Boundary Value ProblemProtein Boundary Value ProblemMinimize free energy – Euler-Lagrange equations for midplaneposition (h) and thickness (2u).Solve equations, match BC’s, & compute deformation energyDissecting the Free EnergyDissecting the Free EnergyApplied Tension Hydrophobic mismatchSpontaneous CurvatureMidplane BendingConclusion: Competition between terms with different radial character!Line Tension & Applied TensionDissecting the Free Energy:Dissecting the Free Energy:Hydrophobic MismatchHydrophobic MismatchHydrophobic mismatchCan tune the hydrophobic mismatch two ways: change the lipidsor mutate the protein.An Effective Potential For ChannelAn Effective Potential For ChannelOpeningOpeningElastic deformation of the membrane is induced by channel.Thickness mismatch leads to a line tension which works againstapplied tensionEffective potential analogous to a nucleation problem.Effective potential for channel radiusApplied tensionExperimental PredictionsExperimental PredictionsCritical tension depends upon lipidlength.Curvature inducing lipids canchange the sign of the effective linetension – stabilizing open state.Amino acid substitutions that tunethe hydrophobic width of thechannel alter gating tension in asystematic fashion.The Curious Case of Voltage GatingThe Curious Case of Voltage GatingThe idea: ion channels(such as for K) are gatedby voltage.Structural biologists havemade huge progress, buttheir successes have lefta wake of paradoxes.RP opinion: careless intreatment of membrane!Membrane mechanicsdistinguishes them.(Mackinnon et al.)Flirting with a Simple Model of VoltageFlirting with a Simple Model of VoltageGatingGatingSame logic – write free energy which reflects response ofchannel AND surrounding membrane.How gating depends uponvoltage, tension (!), lipidcharacter, etc… Testable –SMB bring it on! Two modelshave different consequences.Ear Structure and Function: IonEar Structure and Function: IonChannel GatingChannel Gating(Cochlear function.)Collective response ofmultiple


View Full Document

CALTECH APH 161 - Lecture notes

Documents in this Course
Lecture 2

Lecture 2

12 pages

Lecture 3

Lecture 3

18 pages

Load more
Download Lecture notes
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Lecture notes and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Lecture notes 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?