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

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

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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

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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

BIRTH BIRTH & & FUTURE FUTURE OF OF MULTI-SCALE MULTI-SCALE MODELING OF MACROMOLECULES MODELING OF MACROMOLECULES

http://csb.stanford.edu/levitt http://csb.stanford.edu/levitt

Michael Levitt 13

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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.

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1.0

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1951: PAULING THE GREAT CHEMIST 1951: PAULING THE GREAT CHEMIST

1951 The alpha-helix

1901-1994 1901-1994

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1953: FRANCIS CRICK 1953: FRANCIS CRICK

1916-2004 1916-2004

DNA Model and Experiment

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First protein X-ray structure.

1959: KENDREW AND MYOGLOBIN 1959: KENDREW AND MYOGLOBIN

Scientific American 1961 Painted by artist Irving Geis

1917-1997 1917-1997

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1962: 1962: PERUTZ PERUTZ AND AND HEMOGLOBIN HEMOGLOBIN

The REAL HERO of structural biology.

1914-2002 1914-2002

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1965: PHILLIPS AND LYSOZYME 1965: PHILLIPS AND LYSOZYME

Early supporter of Computational Biology

1924-1999 1924-1999

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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

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LIQUIDS: LIQUIDS: ARGON ARGON & & WATER WATER

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Argon Argon is is like like a a collection collection of

  • f

hard spheres. Each Argon has hard spheres. Each Argon has 12 to 14 neighbors. 12 to 14 neighbors. Water has an open structure. Water has an open structure. Due Due to to tetrahedral tetrahedral geometry, geometry, each water has 4 to 5 neighbors. each water has 4 to 5 neighbors.

Molecular Simulation. Aneesur Rahman

1927-1987 1927-1987

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

SUMMARY SO FAR SUMMARY SO FAR

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  • 2. BIRTH OF

COMPUTATIONAL STRUCTURAL BIOLOGY

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4.3

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KENDREW, ME & ISRAEL KENDREW, ME & ISRAEL

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Nobel Prize in 1962 Gave TV Series in 1964 Sent me to Israel in 1967

BBC TV Winter 1964

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SHNEIOR SHNEIOR LIFSON LIFSON 1914-2001 1914-2001

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Weizmann Institute 1967-68

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BIOLOGY IS DETAILED INTERACTIONS BIOLOGY IS DETAILED INTERACTIONS

Myoglobin 1961 Lysozyme 1966

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MOLECULAR POTENTIAL ENERGY MOLECULAR POTENTIAL ENERGY

U U

Simple Simple sum sum

  • ver many
  • ver many

terms terms

U r

r

+

  • r

U r U

T

All Bonds All Bonds All All Angles Angles All partial charges All partial charges All All Nonbonded Nonbonded pairs pairs All All Torsion Torsion Angles Angles

Hooke Hooke 1635 1635 Fourier Fourier 1768 1768 Van Van der der Waals Waals 1837 1837 Coulomb Coulomb 1736 1736

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MOVING OVER ENERGY SURFACE MOVING OVER ENERGY SURFACEx

Energy, Energy, U Position Position EM: E Energy Minimization drops drops into nto local local minimum. minimum. MD: MD: Molecular Molecular Dynamics ynamics uses uses thermal thermal energy energy to to move move smoothly smoothly over

  • ver surface.

urface. MC: M Monte Carlo Moves are random.

  • random. Accept

ccept with with probability probability exp exp(-U/kT). U/kT).

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NMD: Normal Mode Dynamics NMD: Normal Mode Dynamics vibrates vibrates about about minimum. minimum.

Euclid Euclid 325 325 BC BC Galileo Galileo 1564 1564 Newton Newton 1643 1643 Metropolis Metropolis 1915 1915

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EINSTEIN EINSTEIN* ON 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.

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http://quoteinvestigator.com/2011/05/13/einstein-simple/

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All Non-Hydrogen Atoms 1969 Atom Groups 1975 All Atoms & Electrons 1976 All Atoms & Water 1988

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MACROMOLECULAR ENERGY MINIMIZATION MACROMOLECULAR ENERGY MINIMIZATION

First protein structure refinement

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COMPUTER COMPUTER SIMULATION SIMULATION OF OF PROTEIN PROTEIN FOLDING FOLDING

Fold protein with 1000 steps of minimization. Escape from local minima with normal modes jumps.

GLY GLY

i

ASP ASP VAL VAL ALA ALA

i i+1

i+1

Reduced models

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THEORETICAL STUDIES OF ENZYMIC THEORETICAL STUDIES OF ENZYMIC REACTIONS REACTIONS

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THE THE FIRST FIRST MOVIE MOVIE OF OF PROTEIN PROTEIN DYNAMICS DYNAMICS (1979) (1979)

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PROTEIN MOLECULAR PROTEIN MOLECULAR DYNAMICS IN DYNAMICS IN WATER 1988 WATER 1988

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16.8 16.8

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ACCURATE ACCURATE SIMULATION SIMULATION OF OF PROTEIN PROTEIN DYNAMICS DYNAMICS IN IN SOLUTION SOLUTION

In In Water Water In In Vacuo Vacuo

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ñ-HELIX MOLECULAR ñ-HELIX MOLECULAR DYNAMICS IN DYNAMICS IN WATER 1990 WATER 1990

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

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  • SUMMARY SO FAR

SUMMARY SO FAR

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  • 3. FUTURE: MULTI-

SCALE DYNAMICS OF HUGE STRUCTURES

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16.9

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MARKOV STATE MARKOV STATE DYNAMICS OF RNA DYNAMICS OF RNA POLYMERASE II POLYMERASE II

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Xuhui Xuhui Huang Huang Daniel Daniel Silva Silva

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Jenelle Jenelle Bray Bray Junjie Junjie Zhang Zhang

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COARSE-GRAINED & ALL-ATOM NORMAL OARSE-GRAINED & ALL-ATOM NORMAL MODE DYNAMICS OF ENTIRE RIBOSOME MODE DYNAMICS OF ENTIRE RIBOSOME

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Peter Minary Peter Minary Adelene Adelene Sim Sim

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NATURAL M MOVE M MONTE C CARLO

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 All of

  • f these

these

Natural Moves allow a hierarchy of moves. One calculation can combine all the different scales. Bases Pairs Bases Pairs & Helices

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ANTIBODY HUMANIZATION ANTIBODY HUMANIZATION

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CDR Residues

Antibody

QUEEN

Antibody

CDR Residues

WINTER

Seven employees living in Nevada next to Lake Tahoe.

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BREADTH BREADTH OR LACK OR LACK OF FOCUS? OF FOCUS?

Ivan Ufimtsev Ivan Ufimtsev Nir Nir Kalisman Kalisman

Large Large Complexes. Complexes.

Andrea Andrea Scaiewicz Scaiewicz

Compare Compare Genomes. Genomes.

Yana Gofman Yana Gofman

Membrane Membrane Proteins. roteins. X R X Ray Phase Problem. Problem.

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

SUMMARY SO FAR

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22.5

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LAPTOP LAPTOP 10 10 GB GB 1 1 GHz GHz $4,000 $4,000 2013 2013 HALL HALL 1 1 MB MB 0.1 0.1 MHz MHz $40M $40M 1967 1967 SIZE SIZE MEMORY MEMORY SPEED SPEED COST COST DATE DATE

HOW COMPUTERS HAVE CHANGED HOW COMPUTERS HAVE CHANGED

10,000 10,000 10,000 10,000 10,000 10,000 10,000 10,000 CHANGE CHANGE

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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MOM MOM RINA INA

MY MOTHER, MY WIFE MY MOTHER, MY WIFE

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You know the old saying? “Behind every successful man there is a

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surprised wife surprised wife”

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BEGINNER SEA-KAYAKING ALONE BEGINNER SEA-KAYAKING ALONE

30.3 30.3 Km Km Utö Ornö

Ornö Kyrke Store “Paradise” First Beach Rest Stop Kayak Rental

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IT WAS A PARADISE IT WAS A PARADISE

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ADVICE TO THE YOUNG ADVICE TO THE YOUNG

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BE ORIGINAL BE ORIGINAL BE PERSISTENT BE PERSISTENT BE PASSIONATE BE PASSIONATE BE KIND & GOOD BE KIND & GOOD

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MENTOR IN ISRAEL MENTOR IN ISRAEL

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Shneior Lifson

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MENTORS MENTORS IN IN CAMBRIDGE CAMBRIDGE

Bob Diamond Aaron Klug Francis Crick Max Perutz John Kendrew

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UK UK Ukraine Ukraine Uruguay Uruguay USA USA Russia Russia Singapore Singapore Spain Spain Sweden Sweden Hungary Hungary India India Israel Israel Pakistan Pakistan Canada Canada China China France France Germany Germany

Recent Research Support: NIH, Recent Research Support: NIH, NSF NSF,

, HFSP

HFSP

PAST PAST & & PRESENT PRESENT GROUP GROUP

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PhD Students PhD Students Miriam Hirshberg Miriam Hirshberg Chris Lee Chris Lee Britt Park Britt Park Dave Hinds Dave Hinds Enoch Huang Enoch Huang Jerry Tsai Jerry Tsai Yu Xia Yu Xia Michael Sykes Michael Sykes Rachel Kolodny Rachel Kolodny Nizar Nizar Batada Batada Sergio Sergio Moreno Moreno Dahlia Dahlia Weiss Weiss Gaurav Chopra Gaurav Chopra Adelene Sim Adelene Sim Post Docs Post Docs

  • S. Subbiah
  • S. Subbiah

Valerie Daggett Valerie Daggett Peter Peter David David Mark Mark Gerstein Gerstein Steven Steven Brenner Brenner Boris Fain Boris Fain Chen Keasar Chen Keasar Golan Golan Yona Yona Ram Samudrala Ram Samudrala Tanya Raschke Tanya Raschke Patrice Koehl Patrice Koehl Erik Sandelin Erik Sandelin Chris Summa Chris Summa Erik Lindahl Erik Lindahl Julian Gough Julian Gough Peter Peter Minary Minary Gunnar Schroeder Gunnar Schroeder Karine Bastard Karine Bastard Avraham Samson Avraham Samson Xuhui Xuhui Huang Huang Julie Bernauer Julie Bernauer Alena Alena Shmygelska Shmygelska Mitul Saha Mitul Saha Andrea Scaiewitz Andrea Scaiewitz Jenelle Bray Jenelle Bray Marie Brut Marie Brut Junjie Junjie Zhang Zhang Leonid Pereyaslavets Leonid Pereyaslavets Yana Yana Gofman Gofman Ivan Ufimtsev Ivan Ufimtsev

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Sven Lidin Måns Ehrenberg Jan-Erling Bäckvall Gunnar Karlström Sara Snogerup Linse Astrid Gräslund

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NOBEL COMMITTEE IN CHEMISTRY OBEL COMMITTEE IN CHEMISTRY

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