MOLECULAR DYNAMICS

1

Protein Prediction, 30/06/11, Marc Offman

Introduction - Proteins

All things are made of atoms, and everything that living things do can be understood in terms of the jigglings and wigglings of atoms. [Feynmann Lectures on Physics]

2

Introduction - Proteins

Molecular Dynamics simulations can provide details about molecular motions as a function of time and are widely used to study protein motions at the atomic level. [Karplus, McCammon 2002 and Shaw, Wriggers 2010]

3

Introduction - Proteins

In 1951, Frederick Sanger published the amino acid sequence of bovine insulin. [Sanger, Tuppy 1951]

1951

ww

w.p

hysc

hem

.co.

za

4

1951 Introduction - Proteins

In 1955, Linderstrom-Lang measured the solvent accessibility of the protein residues through Hydrogen Deuterium Exchange.[Linderstrom-Lang 1955]

1955

[Kor

nhab

er e

t al.,

200

8]

5

1955 1951 Introduction - Proteins

The first 3D structures of proteins were published in 1958. The tertiary structure of Myoglobin and Hemoglobin was first solved by Perutz and Kendrew. Both received the Nobel Price in 1962.[Muirhead, Perutz 1961; Kendrew, Phillips 1958]

[Blo

od J

ourn

al; T

he C

ell]

6

1958

Introduction - Proteins

Sequence

7

Introduction - Proteins

Sequence Structure

8

Function

Introduction - Proteins

Sequence Structure

9

Introduction - Proteins

Sequence Structure

Flexibility Function

10

Introduction - Proteins

Sequence Structure

Flexibility Function

11

Introduction - Methods

Sequence Structure

Flexibility Function

12

Protein sequencing

Gene sequencing

Introduction - Methods

Sequence Structure

Flexibility Function

13

Protein sequencing

Gene sequencing

X-RAY NMR

Cryo electron microscopy

Modelling

Introduction - Methods

Sequence Structure

Flexibility Function

14

Protein sequencing

Gene sequencing

X-RAY NMR

Cryo electron microscopy

Modelling

H/D exchange NMR

Molecular Dynamics

Introduction - Methods

Sequence Structure

Flexibility Function

15

Protein sequencing

Gene sequencing

X-RAY NMR

Cryo electron microscopy

Modelling

Experimental essays

Homology modelling

H/D exchange NMR

Molecular Dynamics

1955 1951 Introduction - MD

The Molecular Dynamics method is introduced by Alder and Wainwright in 1957 to study the interactions between solid sphered.[Alder, Wainwright 1957 and 1959]

16

1957 1958

1955 1951 Introduction - MD

The first Molecular Dynamics simulation of a real system was performed in 1974 for liquid water. [Stillinger, Rahman 1974]

17

1958 1958 1974 1957

1958 1957 1955 1951 1974 1977 Introduction - MD

The first Molecular Dynamics simulation of a protein in 1977 by McCammon. 9.2 ps of Bovine Pancreatic Trypsin Inhibitor. [McCammon 1977]

18

Introduction - Time

19

Each flash of this light = 1 second 1 millisecond (ms) = 10-3 seconds 1 microsecond (µs) = 10-6 seconds 1 nanosecond (ns) = 10-9 seconds 1 picosecond (ps) = 10-12 seconds 1 femtoseconds (fs) = 10-15 seconds

Average-sized protein 16 hours of calculations

Introduction - Time

20

Local Motions (10-15 to 10-1 s; fs - ms) - Atomic fluctuations - Side chain motions - Loop motions

Rigid Body Motions (10-9 to 1 s; ns - s)

- Helix motions - Domain motions (hinge bending) - Subunit motions

Large-Scale Motions (10-7 to 104 s; µs - m)

- Helix coil transitions - Dissociation / Association of molecules - Folding and Unfolding

[Theory of Molecular Dynamics Simulations, Swiss Institute of Bioinformatics]

Introduction – MD timeline

21

~10 ps

1977

1977 McCammon 9.2 ps MD simulation.[McCammon 1977]

Introduction – MD timeline

22

~10 ns

1977

A 10 ns Molecular Dynamics Simulation of whole Satellite Tabacco Mosaic Virus.[Freddolino, Schulten 2006]

Today 1977

[http://ww

w.ks.uiuc.edu/G

allery/Movies/]

Introduction – MD timeline

23

~10 µs

1977

A 10 µs MD simulation of a Fast Folding WW Domain computed within 3 months. [Freddolino, Schulten 2008]

Today 2008 1977

[http://ww

w.ks.uiuc.edu/G

allery/Movies/]

Introduction – MD timeline

24

~1 ms

1977

Folding proteins at x-ray resolution, showing comparison of x-ray structures (blue)and last frame of MD simulation (red): (A) simulation of villin at 300 K, (B) simulation of FiP35 at 337 K. 1 ms MD simulation of Bovine Pancreatic Trypsin Inhibitor using a specially designed supercomputer. [Shaw, Wriggers 2010]

2010 2008 1977

Introduction – MD

25

Molecular Dynamics simulations can serve as a powerful tool for elucidating the atomic-level behavior of proteins. [Shaw, Wriggers, 2010]

Introduction – MD

26

Atomic Level

Introduction – MD

27

Quantum Physics ???

Introduction – MD

28

Quantum Physics ???

Introduction – MD

29

~ ~

Approximations !!!

Introduction – MD approximations

The following approximations are usually applied in Molecular Dynamics methods:   The simulation is classical – Newton’s second law  Electron motion is ignored (Born-Oppenheimer approx.)   Force fields are approximate   Long range interactions are omitted beyond a defined cut-off  Boundary conditions are unnatural

30

Introduction – approximations

31

Introduction – approximations

32

Introduction – approximations

33

Classical Physics Quantum Physics

Methods

34

For simplicity an atom is a solid sphere with a point mass and a point charge in its center

Sphere

Point charge and point mass

“This is an atom”

Methods

35

A protein is formed by several atoms.

Amino acid 1

Amino acid 2

Methods

36

Bonds, angles and torsion angles are flexible as proteins are intrinsically flexible molecules

Methods

37

The Force Field

Force fields

38

Atom 2 Atom 1

Force fields

39

Atom 2 Atom 1

Hooke's Law

Force fields

40

Atom 2 Atom 1

Force fields In order to describe molecular movement we need: COORDINATES OF EACH ATOM THROUGH TIME…

41

Force fields

42

[wikipedia]

Force fields

43

[http://www.stanford.edu/~boas/science/protein_design]

Force fields

44

Bonded interactions:   Stretching   Bending   Torsion

Non-bonded interactions:

  Electrostatics   Van der Waals

+

-

[www.ch.embnet.org]

Force fields

45

[www.ch.embnet.org]

Force fields

46

[www.ch.embnet.org]

Force fields

47

[www.ch.embnet.org]

Inproper dihedrals

Force fields

48

[www.ch.embnet.org]

Minimization

49

Most common methods:   Steepest descent   Conjugate gradient

The energy surface of biological systems is VERY COMPLEX Special algorithms are used to reduce the complexity

MD – What’s needed   The system definitions   Identities and coordinates of all atoms   Mass, charge and radii of all atoms   Bonds, angles and torsion angles   Solvent information (which model etc.)

  The initial conditions   Temperature   Velocity   Pressure   Periodic boundary conditions and shape

 Several force fields (protein/dna, lipids, water)

50

Popular MD packages

 Charmm – Chemistry at HARvard Macromolecular Mechanics  Gromacs – GRoning Machine for Chemical Simulations  Amber - Assisted Model Building with Energy Refinement  NAMD – Not Another Molecular Dynamics program

51

MD – Flowchart

52

Experiments vs. MD

53

[http://www.yasara.org/]

Experimental observations (Statistical ensemble averages)

MD Simulation (Time averages)

= ERGODIC THEORY

Applications of MD

 Protein Stability  Protein Flexibility  Conformational Changes  Protein Folding  Protein Docking  Molecular Recognition  Complex Formation and Interactions  Biological Ion Transport  Simulations of systems as large as viruses

54

Water droplet

55

Water droplet on silica 2ns

[http://ww

w.ks.uiuc.edu/]

DNA translocation

56

Alpha-hemolysin used In DNA sequencing

1.2ns

[http://ww

w.ks.uiuc.edu/]

Water Channel

57

Aquaporin 12ns

[http://ww

w.ks.uiuc.edu/]

THANKS   To you for listening!  Burkhard Rost  Rostlab  Alexander von Humboldt Foundation   LRZ  Scalalife

 Maina Bitar for the HS slides that these slides were partially adapted from…  My family ;)

58

MOLECULAR BASIS OF REDUCED GLUCOSYLCERAMIDASE ACTIVITY IN THE

MOST COMMON GAUCHER DISEASE MUTANT, N370S.

59

Most common Gaucher Mutations�

  F213I � �Type 3� N370S � �Type 1� D409H � �Type 2�  L444P � �Type 2� R496H � �Type 1�

[Sawkar et al., 2006]

GBA�

Domain I�

Domain II�

Domain III�

AS

MD better than experiments?  Recently accepted comparison of two experimental papers and our MD analysis

62

[Offman, Futerman 2011]

RMSFs

63

! !

[Offman, Futerman 2010]

More RMSFs

64

![Offman, Futerman 2010]

Flexibility & Interaction

65

![Offman, Futerman 2010]

Hydrogen Bonds & Distances

66

!

[Offman, Futerman 2010]

Hydrogen Bonds & Distances

67

!

[Offman, Futerman 2010]

Active Site

68

![Offman, Futerman 2010]

Active Site – Catalytic Residues

69

!

[Offman, Futerman 2010]

Active Site – Hydrogen Bonds

70

![Offman, Futerman 2010]

Active Site – Loops

71

![Offman, Futerman 2010]

Active Site – Loop Affinity

72

!

[Offman, Futerman 2010]

Active Site – Loops Secondary Structure

73

!

[Offman, Futerman 2010]

Active Site – Integrity

74

!

[Offman, Futerman 2010]

Summary

75

![Offman, Futerman 2010]

THE END

76