Computational Structural Biology

1
Computational Structural Biology

• ECS289L
• Instructor Patrice Koehl

2
Useful Links

• Class web site
• http//www.cs.ucdavis.edu/koehl/Classes/CSB/
• Electronic Notebook
• http//www.cs.ucdavis.edu/koehl/BioEbook/

3
Our Focus Protein Folding
1) Proteins 2) The Cycle of Life 3) What
drives folding?
4
Our Focus Protein Folding
1) Proteins
- Molecules of Life - Diversity - Structure -
Representation - Molecular Graphics - Engineering
5
Proteins The Molecules of Life

• Ubiquitous molecules that are involved in all
• cellular functions
• Communication agents between cells
• Failure of a protein (missing, inactive, )
• can lead to serious health problems
• (prions, )

6
Protein Structure Diversity
1CTF
1TIM
1A1O
1K3R
1NIK
1AON
7
Protein Structure
Structure
Sidechains
Backbone
Sequence .Gly Phe Asp .
8
Protein Structure Variables
Backbone 3 angles per residue j, f and
w Sidechain 1 to 7 angles, c each c has 3
favored values 60o, -60o, 180o.
9
Protein Structure
Primary structure
Secondary Structure
Tertiary Structure
Sequence of Amino acids
Local interactions
Native protein
10
Protein Structure Representation
CPK hard sphere model
Ball-and-stick
Cartoon
11
Molecular Graphics RasMol

• Basic Graphics
• Open file containing molecule structure
• Choose drawing mode
• Rotate, move and scale
• Play with coloring scheme
• Select a region and highlight it
• Select amino acids and highlight in color and
  style

12
Protein Engineering

• Nano Engineering
• - Can make any sequence
• - Really small features (0.1 nm)
• - Molecular machines
• Recruit Proteins for New Tasks
• - Industrial enzymes
• - Bio-remediation
• - Pharmacology
• - Material Sciences

10 nm
13
Our Focus Protein Folding
1) Proteins 2) The Cycle of Life

• Sequence to Function and Back
• Structure is central

14
The Cycle of Life
Structure
Function
Sequence
KKAVINGEQIRSISDLHQTLKK WELALPEYYGENLDALWDCLTG VEYP
LVLEWRQFEQSKQLTENG AESVLQVFREAKAEGCDITI
Evolution
ligand
From Sequence to Function and Back
15
Structure is Central
Structure Space
Protein Sequence Design
Protein Structure Determination
NMR X-Ray Neutron Diffraction Prediction
Directed evolution Computational Design
Sequence Space
16
Structure is Central
Function depends On protein shape
Specific associations Precise reactions
17
Our Focus Protein Folding
1) Proteins 2) The Cycle of Life 3) What
drives folding?

• -Protein Energetics
• Hydrophobic Effect
• Energy landscape

18
Why do proteins fold?
Unfolded State

• Protein backbone is a linear chain
• Chain is self-avoiding
• Protein is closely packed
• Amino Acid preferences
• - inside (hydrophobic)
• / outside (hydrophilic)
• - Specific interactions

Folded State
19
What is an atom?

• Classical mechanics a solid object
• Defined by its position (x,y,z)
• Carries an electric charge (positive or
  negative), usually partial (less than an electron)

20
What is a molecule?
Non-bonded pair
Torsion angles Are 4-body
Angles Are 3-body
Bonds Are 2-body
21
Forces between atoms
Non bonded interactions

• Strong bonded interactions

r
b
q
q1
q2
f
22
Interaction with solvent

• - Hydrophobic effect
• (entropic effect)
• Interaction with ions
• Concentration?

23
Energy Landscape
1 ms to 1s
Barrier crossing time expBarrier Height
1 ms
Barrier Height
Unfolded State Expanded, disordered
Molten Globule Compact, disordered
Native State Compact, Ordered