1. The document describes a computational framework for interacting with physical molecular models of polypeptide chains. It involves developing physical models of proteins using 3D printing and interfacing them with computational tools. 2. The framework aims to enable new scientific discovery through a tactile, geometric approach that is complementary to existing computational modeling of proteins. 3. The physical models are parameterized so they can be customized based on protein data and interfaced with computer simulations, allowing comparison to online databases.

1. 1
A Computational Framework
for Interacting with Physical
Molecular Models of the
Polypeptide Chain
Promita Chakraborty
Mar 26, 2014
PhD Dissertation Final Defense
Blacksburg, Virginia Tech
Peppytides

2. 2
A computational paradigm
1 2 3
• N: data from native protein structures, experimental analysis and observations
• C: existing computational models
• P: form-specific physical models of proteins

3. Processes 1 and 2
3

4. 4
Folding of polypeptides
Polypeptide, before and after folding
Source: http://en.wikipedia.org/wiki/Protein_folding
pid: 2R73,Trichosurin, milk whey protein

5. 5
Spatial-reasoning in humans
David Baker Lab, Univ. of Washington

6. 6
A new way of looking at
the old problem
• Tactile, geometrical, spatial approach
• Complementary to computational
approach
• Enable new scientific discovery
Khatib, Baker et al. Crystal structure of a monomeric retroviral protease solved by protein
folding game players, Nature Structural &. Mol. Biol., 18 (2011)

7. Processes 3 and 4
7

8. 8
93,000,000 times
magnified
O
H
N
Peppytide Model

9. 9
Existing models
CPK models
Dreiding stereomodel
Ball-and-stick
Center for
BioMolecular
Modeling, Milwaukee
School of Engineering
http://www.
3dmoleculardesigns.com/
Scripps Physical Model
Service, Scripps Research
Institute
http://models.scripps.edu/
beta sheet
alpha helix
DNA double helix
Gillet, Olson et al. Tangible Interfaces for Structural Molecular Biology,
Structure, 13 (2005)

10. 10
-62°
ψ
ϕ
-42°
-118°
ψ ϕ
138°
In PyMol
Configuration change of ψ and ϕ: α-helix→β-sheet
α-helix β-sheet
ψ ϕ
Peppytides

11. 11
Polypeptides
AA1 AA2 AA3 AA4
Repeating homopolymer of amino acid units:
Alternating copolymer of amide and alpha carbon units:

12. 12
Protein data to model

13. 13
Atom-radii = 0.6 RVDW
Atom-radii = 0.7 RVDW
Atom-radii = 0.8 RVDW
"
Measured at 5˚ intervals
Ramachandran plot generated using
~80,000 structures from Protein Data
bank

14. 14
Constrained bond angles:
How magnets work to simulate rotational
barrier?
Ψ
(Psi)ᶲ
Φ
(Phi)

15. 15
Measuring the forces experienced by
the rotation-barrier-magnets

16. 16
Energy plot (OPLS force field)
Peppytides at 0.7 RVDW with rotational barrier constraints
Ramachandran plots:A comparison
PDB data
Chakraborty and Zuckermann. Coarse-grained, foldable,
physical model of the polypeptide chain. PNAS,110 (33), (2013)

17. 17
Hydrogen bond
• Representing with magnets
• acceptor/donor as N/S pole
O–N distance is typically
3.00 ± 0.12 Å, from an α-
helix crystal structure
In the Peppytide model, the
O–N distance is 1.17 ̋ ±
0.04 ̋ (equivalent to 3.18 ±
0.11 Å)

18. 18
Side Chains
• Role of backbone
✓ Role of side-chains
Alanine
Valine
18

19. 19
α
310
π
Helix
19

20. 20
18.4 Å
Alpha helix
6.75 (~18.362 Å)
alphaC1 - alphaC13
pid: 2ZTA chain B {AA-16}
KNYHLENEVARLKKL

21. 21
Parallel beta sheet

22. 22
Measuring N1 to N5
13.4 Å
12.9 Å
4.853 ± 0.044
(~13.202 ± 0.121Å)
4.853 ± 0.103
(~13.202 ± 0.281Å)
pid: 202J
Parallel beta sheet
22

23. 23
Antiparallel beta sheet

24. 24
Beta turns
Type I
Type I'
Type II
Type II'

25. 25
• beta beta alpha motif
• pid: 1FSD (28 amino acids)
N-term
C-term
Dahiyat, and Mayo, De Novo Protein Design: Fully Automated Sequence Selection. Science, 278(82) (1997)
FSD-1 denovo structure

26. 26
pid: 1VZM, chain A 45 amino acids
N-term
C-term
Fish Osteocalcin

27. Processes 5 and 6
27

28. 28
Physical-digital Interfacing
Generic
Physical
model
View
Geometry Orientation
Parameterizing
Digital
model
Automated Physical model
for specific structure

29. 29
Interfacing with computer
• User-friendly printing of
customized and
parameterized physical
models
• Molecular simulation for the
physical model
• Comparison with online
databases
Collaboration with AutoDesk Inc.

30. 30
Design of workflow
Motto:
Design,
Print,
Build
and
Simulate

31. 31
Peptide structure represented
by series of dihedral angles
• It is possible to describe the backbone structure by a sequence of phi psi angles?*
Residue #
Phi
Psi
1
-65
-40
2
-65
-40
...
-65
-40
Peptide bond angle
table representation
Backbone trace of
the same
polypeptide chain
A polypeptide
chain s native
conformation
*Ranganathan, Izotov, Kraka, and Cremer. Classification of Supersecondary Structures in Proteins Using the Automated Protein Structure Analysis Method. Arxiv preprint. (2008)
31

32. 32
Model Checking
• A context free grammar

33. 33
Data Flow Framework
1
2
3
4

34. 34
Examples on
Augmented Reality
Art Olson Lab,The Scripps Research Inst.
Future Work

35. 35
Augmented Reality
DuploTrack: Object
tracking with lego blocks using
Microsoft Kinect camera
Gupta et al. DuploTrack: A Realtime System for
Authoring and Guiding Duplo Block Assembly.,
UIST, (2012)
Autodesk 123D Catch
Scan-Modify-Print philosophy
To:
Structure determination -
Human-scale abstraction -
3D-print -
Fold

36. 36
Two Self folding techniques
With permission from:
Skylar Tibbits
Dept. of Architecture,
MIT

37. 37
Outreach/user study
At Lawrence Hall of Science
museum, UC Berkeley
In collaboration with Maia Werner-Avidon and Lisa Newton
at Lawrence Hall of Science museum, UC Berkeley

38. 38
How to make them?
Open source
STL files available at www.peppytide.org
Make Magazine -- Projects
http://makezine.com/projects/peppytides/

39. 39
Summary
• Physical-digital interfacing
• Enabling CAD-
Bioplatform-3DPrinting
• Information handling
• Open source
• Enabling verification of
DeNovo computational
models
• Enabling scientific discovery

40. 40
Acknowledgments
• Prof. Alexey Onufriev, Virginia Tech (Chair Co-advisor)
• Dr. Ronald Zuckermann (Co-advisor)
• Prof. Joseph DeRisi, UCSF (Committee member)
• Prof. Naren Ramakrishnan (Committee member)
• Prof. Liqing Zhang (Committee member)
• Molecular Foundry, Lawrence Berkeley National Laboratory
• Lawrence Hall of Science Museum, UC Berkeley
• Molecular Graphics and Computation Facility at UC Berkeley
• Industry Collaboration and support by Autodesk Inc.
This work was performed at the Molecular Foundry, Lawrence Berkeley National Laboratory, and was supported by the Defense
Threat Reduction Agency and the Office of Science, Office of Basic Energy Sciences, Scientific User Facilities Division, of the
U.S. Department of Energy under Contract No. DE-AC02—05CH11231.

41. 41
Extras

42. 42
93,000,000 times magnified
O
H
N
Peppytide Chain

43. 43
Trade off:
Van der Waals radius
Vs.
Covalent radius
Benzene
0.1 VDWr 0.35 VDWr 0.5 VDWr 0.65 VDWr
0.7 VDWr 0.8 VDWr 0.9 VDWr 1.0 VDWr
Version
#
*VDWr
Ver1
0.5 / 0.35
Ver2.1
0.8
Ver2.2
0.7
Bondi Radius