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Life is Different: it is inherited

Biology is inherited. Information is passed by handfuls of atoms in the genetic code. A few atoms in the proteins built from the code change macroscopic function. Indeed, a few atoms often control biological function in the same sense that a gas pedal controls the speed of a car. Biological questions then are most productive when they are asked in the context of evolution. What function does a system perform? How is the system built to perform that function? What forces are used to perform that function? How are the modules that perform functions connected to make the machinery of life. Physiologists have shown that much of life is a nested hierarchy of devices, one on top of another, linking atomic ions in concentrated solutions to current flow through proteins, current flow to voltage signals, voltage signals to changes in current flow, all connected to make a regenerative system that allows electrical action potentials to move meters, under the control of a few atoms. The hierarchy of devices allows macroscopic properties to emerge from atomic scale interactions. The structures of biology create these devices. The concentration and electrical fields of biology power these devices, more than anything else. The resulting organisms reproduce. Evolution selects the organisms that reproduce more and thereby selects the devices that allow macroscopic control to emerge from the atomic structures of genes and proteins and their motions.

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Life is Different: it is inherited

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  1. Life is Different: it is inheritedBob Eisenberg Department of Applied MathematicsIllinois Institute of Technology Department of Physiology and BiophysicsRush University Chicago

  2. Thanks to Jinn-Liang Liu劉晉良 For a very special FriendshipandCollaboration!

  3. 國立清華大學計算與建模科學研究所 Workshop on Biological Ion Channels ICMS, National Tsin Hua University Organized by Jinn-Liang Liu劉晉良

  4. Life is special because it is inherited from a tiny number of atoms And the central question of biology is How is this possible?

  5. How can a few thousand atoms conceivably control 1025 atoms?

  6. Ompf G119D A few atoms make a BIG Difference Glycine Greplaced by Aspartate D OmpF 1M/1M G119D 1M/1M OmpF0.05M/0.05M G119D 0.05M/0.05M Structure determined by Raimund Dutzlerin Tilman Schirmer’s lab Current Voltage relation determined by John Tang in Bob Eisenberg’s Lab

  7. How can a few thousand atoms conceivably control 1025 atoms? Traditional Statistical Mechanics says this is impossible! where and specifies the radius of the small spherical volume over which the spatial average takes place.

  8. How can a few thousand atoms conceivably control 1025 atoms? The thousand atoms of one gene occupy say 10-27 m3 The volume of a person might be 1m3 Volume of USAChina 1m high is 1013m3 Fraction of space of a gene is about 10-27 Fraction of Space of One Person in USA is 10-13 1 m3 has no effect in USA 1 gene should have no effect

  9. Answer:Biology is made of Devicesand they span the scales Organelle 10-6m Organ10-1 m Molecule 10-8 m ATOM 10-10 m Cell 10-5m Tissue 10-3 m Cell 10-5m ORGANISM1 m

  10. How can a few thousand atoms conceivably control 1025 atoms? ANSWER:by forming a HIERARCHY of DEVICES

  11. Different Kind of Averaging in Device • Definition of a DeviceOutput is Perfectly Correlated with Input • Averaging in a Device Creates a Perfectly Correlated Replica of the Input Notequal

  12. Hierarchy of Life

  13. Biology is made of Devicesand they are Multiscale

  14. One Cell contains many Devices

  15. Example: Real Biological System A Nerve Cell is a Hierarchy of Devices

  16. Nerve Signal is “Action Potential (waveform)

  17. Channels are Source of Signal

  18. Start with Voltage Sensor

  19. Voltage Sensor Structure (NOT conduction channel) Emerging Consensus …. Vargas, E., Yarov-Yarovoy, V., Khalili-Araghi, F., Catterall, W. A., Klein, M. L., Tarek, M., Lindahl, E., Schulten, K., Perozo, E., Bezanilla, F. & Roux, B.An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. The Journal of General Physiology 140, 587-594 (2012).

  20. Voltage Sensor Structure (NOT conduction channel) Emerging Consensus …. Vargas, E., Yarov-Yarovoy, V., Khalili-Araghi, F., Catterall, W. A., Klein, M. L., Tarek, M., Lindahl, E., Schulten, K., Perozo, E., Bezanilla, F. & Roux, B.An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. The Journal of General Physiology 140, 587-594 (2012).

  21. Perhaps the firstConsistent Model of a Protein Machine Francisco Bezanilla Allen Tzyy-Leng Horng Chun Liu 柳 春 Bob Eisenberg 洪子倫

  22. Voltage Sensor works by Charge Injection through a fluid dielectric of side chains intracellular extracellular Figure 1. Geometric configuration of the reduced mechanical model including the attaVoltage sensor works by charge injection through a fluid dielectric of side chains.chmentsof arginines to the S4 segment.

  23. Fitting Data Figure 9. (a) Time courses of subtracted gating current [A1]with voltage rising from -90mV to VmV at t=10, holds on till t=150, and drops back to -90mV, where V=-62, -50, … -8 mV. (b) τ2 versus V compared with experiment [7].

  24. Fitting Data Figure 3. (a) QV curve and comparison with [7]. Steady-state distributions for Na, Cl and arginines at (b) V=-90mV, (c) V=-48mV, (d) V=-8mV.

  25. Current is Conserved INPUT Voltage Clamp Ions t Electric Field OUTPUTCurrent including

  26. Nerve Signaling is a Hierarchy of Devices

  27. Channels are Source of Signal

  28. How do ions move through channels? About 200 papers since 1986

  29. Working Hypothesis bio-speak: Crucial Biological Adaptation is Crowded Ions and Side Chains Biology occurs in concentrated >0.3 M mixtures of spherical charges NOT IDEAL AT ALL Poisson Boltzmann does NOT fit data!!Solutions are extraordinarily concentrated >10M where they are most important, near DNA, enzyme active sites, and channels and electrodes of batteries and electrochemical cells. Solid NaCl is 37M

  30. Solutions are Extraordinarily Concentrated >10M Solid NaCl is 37Mwhere they are most important, DNA, enzyme active sites, channels and electrodes of batteries and electrochemical cells

  31. Active Sites of Proteins are Very Charged 7 charges ~ 20M net charge = 1.2×1022 cm-3 liquidWater is 55 Msolid NaCl is 37 M + + + + + - - - - Selectivity Filters and Gates of Ion Channels are Active Sites Physical basis of function OmpF Porin Hard Spheres Na+ Ions are Crowded K+ Ca2+ Na+ Induced Fit of Side Chains K+ 4 Å Figure adapted from Tilman Schirmer

  32. Crowded Active Sitesin 573 Enzymes Jimenez-Morales,Liang, Eisenberg

  33. Poisson Fermi Approach to Ion Channels . 劉晉良 Jinn-Liang Liu discovered role of SATURATIONBob Eisenberg helped with applications

  34. Biological Ion Channels (Crystal Structures) • Gramicidin A • Sodium/Calcium Exchanger (NCX) • Transient Receptor Potential Channel (TRPV1) • Voltage-Gated Calcium Channel (CaVAb) • Potassium Channel (KcsA) • Jinn-Liang Liu et al are working on these channel structures from Protein Data Bank. Slide by Jinn Liang Liu

  35. Motivation Natural Description of Crowded Charge is a Fermi Distributiondesigned to describe saturation Simulating saturationby interatomic repulsion (Lennard Jones) is a significant mathematical challengeto be side-stepped if possible

  36. Motivation Largest Effect of Crowded Chargeis Saturation Saturation cannot be described at all by classical Poisson Boltzmann approach and is described in a (wildly) uncalibrated way by present day Molecular Dynamics

  37. Motivation Fermi Description is designed to deal with Saturation of Concentration Simulating saturationby interatomic repulsion (Lennard Jones) is a significant mathematical challengeto be side-stepped if possible

  38. Fermi DescriptionofSaturation of Volumeby Spherical Ions Fermi (like) Distribution J.-L. Liu J Comp Phys (2013) 247:88

  39. ChallengeCan Simplest Fermi Approach • Describe ion channel selectivity and permeation? • Describe non-ideal properties of bulk solutions? There are no shortage of chemical complexities to include, if needed! Classical Treatments of Chemical Complexities

  40. Fermi Description usesEntropy of Mixture of Spheresfrom Combinatoric Analysis W is the mixing entropy of UNEQUAL spheres with N available NON-UNIFORM sites Connection to volumes of spheres and voids, and other details are published in 8 papers J Comp Phys (2013) 247:88 J Phys Chem B (2013) 117:12051 J Chem Phys (2014) 141: 075102 J Chem Phys, (2014) 141: 22D532 Phys Review E (2015) 92: 012711 Chem Phys Ltrs, (2015) 637 1-6 Phys Rev E, (2016) 94 012114 Mol. Based Math. Biol. 2017; 5:116–124,

  41. Voids are Needed Electro-Chemical Potentialand Void Volume It is impossible to treat all ions and water molecules as hard spheres and at the same time have Zero Volume of interstitial Voidsbetween all particles.

  42. Fermi(like) Distribution Fermi(like)Distribution is aQuantitative Statement of Charge-Space Competition Simulated and compared to experiments in > 35 papers of Boda, Henderson, et al, also givesGibbs Fermi FunctionalJ Comp Phys, 2013 247:88; J Phys Chem B, 2013 117:12051so the Fermi approach Can be embedded in the Energy Variational Formulation EnVarA developed by Chun Liu, more than anyone else

  43. Charge-Space Competition MonteCarloMethods Dezső Boda Wolfgang Nonner Doug Henderson Bob Eisenberg More than 35 papers are available at ftp://ftp.rush.edu/users/molebio/Bob_Eisenberg/reprints

  44. PNPF Poisson-Nernst-Planck-Fermi Implemented fully in 3D Code to accommodate 3D Protein Structures Flow Force approximates dielectric of entire bulk solution including correlated motions of ions, following Santangelo 20061 used by Kornyshev 20112 with Liu’s corrected and consistent Fermi treatment of spheres We introduce3,4two second order equations and boundary conditions That give the polarization charge density 3D computation is facilitated by using 2nd order equations 1PhysRev E (2006)73:041512 2PhysRev Ltrs (2011) 106:046102 3JCompPhys (2013) 247:88 4J PhysChem B (2013) 117:12051

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