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 - 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
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 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
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
36
Bonds, angles and torsion angles are flexible as proteins are intrinsically flexible molecules
Force fields In order to describe molecular movement we need: COORDINATES OF EACH ATOM THROUGH TIME…
41
Force fields
44
Bonded interactions: Stretching Bending Torsion
Non-bonded interactions:
Electrostatics Van der Waals
+
-
[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
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
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]
MD better than experiments? Recently accepted comparison of two experimental papers and our MD analysis
62
[Offman, Futerman 2011]