1,Figure by Raimund Dutzler,2,Channels form a class of Biological Systems that can be analyzed with Physics as Usual Physics-Mathematics-Engineering are the proper language for Ion Channels in my opinion,ION CHANNELS: Proteins with a Hole,3,Physics as Usual along with Biology as Usual,Ion Channels can be analyzed with,“Why think? . . . Exhaustively experiment. Then, think” Claude Bernard Appropriate when nothing was known of Inverse Problems!,Cited in The Great Influenza, John M. Barry, Viking Penguin Group 2004,4,5,Ion Channels are the Main Molecular Controllers “Valves” of Biological Function,Figure by Raimund Dutzler,6,Channels control flow of Charged Spheres Channels have Simple Invariant Structure on the biological time scale. Why cant we predict the movement of Charged Spheres through a Hole?,ION CHANNELS as Physical Devices,7,Physical Characteristics of Ion Channels Natural Nanodevices,Figure by Raimund Dutzler,8,Channels Control Macroscopic Flow with Atomic Resolution,ION CHANNELS as Technological Objects,9,Ion Channels are Important Enough to be Worth the Effort,10,Goal: Predict Function From Structure given Fundamental Physical Laws,11,Current in One Channel Molecule is a Random Telegraph Signal,Gating: Opening of Porin Trimer,John Tang Rush Medical Center,13,Single Channel Currents have little variance,John Tang Rush Medical Center,14,Lipid Bilayer Setup Recordings from a Single Molecule,Axopatch,15,Patch clamp and Bilayer apparatus clamp ion concentrations in the baths and the voltage across membranes.,Patch Clamp Setup Recordings from One Molecule,16,Voltage in baths Concentration in baths Fixed Charge on channel protein,Current depends on,John Tang Rush Medical Center,Bilayer Setup,17,Current depends on type of ion Selectivity,John Tang Rush Medical Center,Bilayer Setup,18,Goal: Predict Function From Structure given Fundamental Physical Laws,19,Structures Location of charges are known with atomic precision (0.1 ) in favorable cases.,20,Charge Mutation in Porin,Ompf,Structure determined by x-ray crystallography in Tilman Schirmers lab Figure by Raimund Dutzler,21,Goal: Predict Function From Structure given Fundamental Physical Laws,22,But What are the Fundamental Physical Laws?,23,Verbal Models Are Popular with Biologists but Inadequate,24,James Clerk Maxwell “I carefully abstain from asking molecules where they start I only count them., avoiding all personal enquiries which would only get me into trouble.” Royal Society of London, 1879, Archives no. 188 In Maxwell on Heat and Statistical Mechanics, Garber, Brush and Everitt, 1995,25,I fear Biologists indulge themselves with verbal models of molecules where Maxwell abstained,26,Verbal Models are Vague and Difficult to Test,27,Verbal Models lead to Interminable Argument and Interminable Investigation,28,thus, to Interminable Funding,29,and so Verbal Models Are Popular,30,Can Molecular Simulations serve as “Fundamental Physical Laws”?,Only if they count correctly !,31,It is very difficult for Molecular Dynamics to count well enough to reproduce Conservation Laws (e.g., of number, energy) Concentration (i.e., number density) or activity Energy of Electric Field Ohms law (in simple situations) Ficks law (in simple situations) Fluctuations in number density (e.g., entropy),32,Can Molecular Simulations serve as “Fundamental Physical Laws”?,Only if Calibrated!,33,Calibrated Molecular Dynamics may be possible,MD without Periodic Boundary Conditions HNC HyperNetted Chain,Pair Correlation Function in Bulk Solution,Saraniti Lab, IIT: Aboud, Marreiro, Saraniti & Eisenberg,34,Calibrated Molecular Dynamics may be possible,MD without Periodic Boundary Conditions BioMOCA Equilibrium Monte Carlo (ala physical chemistry),Pair Correlation Function in Bulk Solution,van der Straaten, Kathawala, Trellakis, Eisenberg & Ravaioli,35,36,Essence of Engineering is knowing What Variables to Ignore! WC Randels quoted in Warner IEEE Trans CT 48:2457 (2001),Until Mathematics of Simulations is available we take an Engineering Approach,37,What variables should we ignore when we make low resolution models? How can we tell when a model is helpful?,Use the scientific method Guess and Check! Intelligent Guesses are MUCH more efficient Sequence of unintelligent guesses may not converge! (e.g., Rate/State theory of channels/proteins),38,Use the scientific method Guess and Check! Intelligent Guesses are MUCH more efficient When theory works, need few checks guesses are almost as good as experiments.,Mechanical Engineering, Electricity, Computer Science, Hydrodynamics,in,39,Use Theory of Inverse Problems to replace or optimize “Guess and Check” 1) Measure only what can be measured (e.g., not two resistors in parallel). 2) Measure what determines important parameters. 3) Use efficient estimators. 4) Use estimators with known bias 5) no matter what the theory, Be clever in estimation,40,Channels are only Holes Why cant we have a fully successful theory