BIRTH BIRTH & & FUTURE FUTURE OF OF MULTI-SCALE - PowerPoint PPT Presentation

BIRTH BIRTH & & FUTURE FUTURE OF OF MULTI-SCALE MULTI-SCALE MODELING OF MACROMOLECULES MODELING OF MACROMOLECULES Nobel L Lectures, S Stockholm 8 December 2013 8 December 2013 Michael Levitt Michael Levitt Structural Biology & Computer Science Structural Biology & Computer Science Stanford Stanford http://csb.stanford.edu/levitt http://csb.stanford.edu/levitt � Michael Levitt 13

SUMMARY SUMMARY 1. How It All Began. 2. Birth of Computational Structural Biology. 3. Future: Multi-Scale Dynamics of Huge Systems. 4. Some General Thoughts. � Michael Levitt 13

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1951: PAULING THE GREAT CHEMIST 1951: PAULING THE GREAT CHEMIST 1951 The alpha-helix 1901-1994 1901-1994 � Michael Levitt 13

1953: FRANCIS CRICK 1953: FRANCIS CRICK 1916-2004 1916-2004 DNA Model and Experiment � Michael Levitt 13

1959: KENDREW AND MYOGLOBIN 1959: KENDREW AND MYOGLOBIN Scientific American 1961 1917-1997 1917-1997 First protein X-ray structure. Painted by artist Irving Geis � Michael Levitt 13

1962: 1962: PERUTZ PERUTZ AND AND HEMOGLOBIN HEMOGLOBIN The REAL HERO of structural biology. 1914-2002 1914-2002 � Michael Levitt 13

1965: PHILLIPS AND LYSOZYME 1965: PHILLIPS AND LYSOZYME 1924-1999 1924-1999 Early supporter of Computational Biology � Michael Levitt 13

1943-1945: LOS ALAMOS 1943-1945: LOS ALAMOS The Birth of the Monte Carlo Method. http://trace.ntu.ac.uk/frame2/articles/borg/JvN.html http://trace.ntu.ac.uk/frame2/articles/borg/JvN.html � Michael Levitt 13

LIQUIDS: LIQUIDS: ARGON ARGON & & WATER WATER Aneesur Rahman 1927-1987 1927-1987 Argon Argon is is like like a a collection collection of of Water has an open structure. Water has an open structure. hard spheres. Each Argon has hard spheres. Each Argon has Due Due to to tetrahedral tetrahedral geometry, geometry, 12 to 14 neighbors. 12 to 14 neighbors. each water has 4 to 5 neighbors. each water has 4 to 5 neighbors. Molecular Simulation. � Michael Levitt 13

SUMMARY SO FAR SUMMARY SO FAR � 1. How It All Began. 2. Birth of Computational Structural Biology. 3. Future: Multi-Scale Dynamics of Huge Systems. 4. Some General Thoughts. � Michael Levitt 13

2. BIRTH OF COMPUTATIONAL STRUCTURAL BIOLOGY 4.3 � Michael Levitt 13

KENDREW, ME & ISRAEL KENDREW, ME & ISRAEL Nobel Prize in 1962 Gave TV Series in 1964 Sent me to Israel in 1967 BBC TV Winter 1964 � Michael Levitt 13

SHNEIOR SHNEIOR LIFSON LIFSON 1914-2001 1914-2001 Weizmann Institute 1967-68 � Michael Levitt 13

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BIOLOGY IS DETAILED INTERACTIONS BIOLOGY IS DETAILED INTERACTIONS Myoglobin 1961 Lysozyme 1966 � Michael Levitt 13

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MOLECULAR POTENTIAL ENERGY MOLECULAR POTENTIAL ENERGY U U All Angles All Angles All Bonds All Bonds Hooke Hooke 1635 1635 U All Torsion All Torsion Angles Angles T Fourier Fourier 1768 1768 U r All All Nonbonded Nonbonded pairs pairs r Van Van der der Waals Waals 1837 1837 r - + Simple sum Simple sum U over many over many All partial charges All partial charges terms terms Coulomb Coulomb 1736 1736 r � Michael Levitt 13

MOVING OVER ENERGY SURFACE MOVING OVER ENERGY SURFACE x EM: E Energy Minimization drops into drops nto local local minimum. minimum. Euclid Euclid 325 325 BC BC Energy, U NMD: Normal Mode Dynamics NMD: Normal Mode Dynamics Energy, vibrates about vibrates about minimum. minimum. Galileo 1564 Galileo 1564 MD: MD: Molecular Molecular Dynamics ynamics uses uses Position Position thermal energy thermal energy to to move move smoothly over smoothly over surface. urface. Newton Newton 1643 1643 MC: M Monte Carlo Moves are random. random. Accept ccept with with exp( - � U/kT). probability exp probability U/kT). Metropolis Metropolis 1915 1915 � Michael Levitt 13

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EINSTEIN * ON EINSTEIN ON SIMPLIFICATION SIMPLIFICATION “Everything Should Be Made As Simple “Everything Should Be Made As Simple As As It It Can Can Be, Be, But But Not Not Simpler” Simpler” *Einstein may have crafted this aphorism, but there is no direct evidence in his writings. He did express a similar idea in a lecture but not concisely. Roger Sessions was a key figure in the propagation of the saying. In fact, he may have crafted it when he attempted to paraphrase an idea imparted by Einstein. http://quoteinvestigator.com/2011/05/13/einstein-simple/ � Michael Levitt 13

All Non-Hydrogen Atoms 1969 Atom Groups 1975 All Atoms & Electrons 1976 All Atoms & Water 1988 � Michael Levitt 13

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MACROMOLECULAR ENERGY MINIMIZATION MACROMOLECULAR ENERGY MINIMIZATION First protein structure refinement � Michael Levitt 13

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COMPUTER COMPUTER SIMULATION SIMULATION OF OF PROTEIN PROTEIN FOLDING FOLDING GLY GLY ALA ALA � i � i � i+1 i+1 ASP ASP VAL VAL Reduced models Fold protein with 1000 steps of minimization. Escape from local minima with normal modes jumps. � Michael Levitt 13

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THEORETICAL STUDIES OF ENZYMIC REACTIONS THEORETICAL STUDIES OF ENZYMIC REACTIONS � Michael Levitt 13

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THE THE FIRST FIRST MOVIE MOVIE OF OF PROTEIN PROTEIN DYNAMICS DYNAMICS (1979) (1979) � Michael Levitt 13 � Michael Levitt 13

PROTEIN MOLECULAR PROTEIN MOLECULAR DYNAMICS IN DYNAMICS IN WATER 1988 WATER 1988 16.8 16.8 � Michael Levitt 13

ACCURATE ACCURATE SIMULATION SIMULATION OF OF PROTEIN PROTEIN DYNAMICS DYNAMICS IN IN SOLUTION SOLUTION In In Vacuo Vacuo In In Water Water � Michael Levitt 13

ñ-HELIX MOLECULAR ñ-HELIX MOLECULAR DYNAMICS IN DYNAMICS IN WATER 1990 WATER 1990 � Michael Levitt 13

SUMMARY SO FAR SUMMARY SO FAR � 1. How It All Began. � 2. Birth of Computational Structural Biology. 3. Future: Multi-Scale Dynamics of Huge Systems. 4. Some General Thoughts. � Michael Levitt 13

3. FUTURE: MULTI- SCALE DYNAMICS OF HUGE STRUCTURES 16.9 � Michael Levitt 13

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MARKOV STATE MARKOV STATE DYNAMICS OF RNA DYNAMICS OF RNA POLYMERASE II POLYMERASE II Xuhui Xuhui Huang Huang Daniel Daniel Silva Silva � Michael Levitt 13

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Junjie Junjie Zhang Zhang Jenelle Jenelle Bray Bray � Michael Levitt 13

COARSE-GRAINED & ALL-ATOM NORMAL OARSE-GRAINED & ALL-ATOM NORMAL MODE DYNAMICS OF ENTIRE RIBOSOME MODE DYNAMICS OF ENTIRE RIBOSOME � Michael Levitt 13

Peter Minary Peter Minary Adelene Adelene Sim Sim � Michael Levitt 13

NATURAL M MOVE M MONTE C CARLO Natural Moves allow a hierarchy of moves. One calculation can combine all the different scales. Bases Pairs Bases Pairs & Helices Move any part of system: Move any part of system: Atoms Atoms Nucleotides Nucleotides Base Base Pairs Pairs Hairpin Helices Hairpin Helices Many Helices together Many Helices together All of All of these these � Michael Levitt 13

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ANTIBODY HUMANIZATION ANTIBODY HUMANIZATION Seven employees living in Nevada next to Lake Tahoe. Antibody Antibody CDR CDR Residues Residues WINTER QUEEN � Michael Levitt 11

- Compare Compare X Ray Phase X R Andrea Andrea Scaiewicz Scaiewicz Ivan Ufimtsev Ivan Ufimtsev Genomes. Genomes. Problem. Problem. BREADTH BREADTH OR LACK OR LACK OF FOCUS? OF FOCUS? Membrane Membrane Large Large Nir Kalisman Nir Kalisman Yana Gofman Yana Gofman Complexes. Complexes. Proteins. roteins.

SUMMARY SO FAR SUMMARY SO FAR � 1. How It All Began. � 2. Birth of Computational Structural Biology. � 3. Future: Multi-Scale Dynamics of Huge Systems. 4. Some General Thoughts. � Michael Levitt 13

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HOW COMPUTERS HAVE CHANGED HOW COMPUTERS HAVE CHANGED DATE DATE COST COST SPEED SPEED MEMORY MEMORY SIZE SIZE 1967 1967 $40M $40M 0.1 MHz 0.1 MHz 1 MB 1 MB HALL HALL 2013 2013 $4,000 $4,000 1 GHz 1 GHz 10 GB 10 GB LAPTOP LAPTOP CHANGE CHANGE 10,000 10,000 10,000 10,000 10,000 10,000 10,000 10,000 If cars were like computers, then a new Volvo would cost $3, would have a top speed of 1,000,000 Km/hr, would carry 50,000 adults and would park in a shoebox. � Michael Levitt 13

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MY MOTHER, MY WIFE MY MOTHER, MY WIFE MOM MOM RINA INA � Michael Levitt 13

You know the old saying? “Behind every successful man there is a surprised wife surprised wife” � Michael Levitt 13

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� Michael Levitt 13

BEGINNER SEA-KAYAKING ALONE BEGINNER SEA-KAYAKING ALONE Ornö Kyrke Ornö Store “Paradise” First Beach Rest Stop Utö 30.3 30.3 Km Km Kayak Rental � Michael Levitt 13

IT WAS A PARADISE IT WAS A PARADISE � Michael Levitt 13