Download Insights into Drug Design Through Structural

Protein Structure Review and Refinement Introduction
Brian Bahnson
Dept of Chemistry & Biochemistry, University of Delaware
Proteins are made by linking amino acids
Several Ways to Visualize Amino Acids
20 common amino acids
Primary Sequence
Secondary Structure
-helix
double headed arrows indicate hydrogen bonds
H
O
N
O
C
N
R
H
R
H
C
N
O
O
R
H
C
N
C
N
R
H
O
R
H
O
C
N
O
C
N
R
H
R
H
C
N
O
O
C
N
R
H
anti-parallel -sheet
H
O
N
N-term
C
N
R
H
R
H
C
O
C
N
R
H
R
N
C
O
O
H
R
O
H
R
O
N
H
C
C
C-term
C
N
C
N
N
R
C
N
O
O
H
R
O
H
R
parallel -sheet
H
O
N
N-term
C
N
R
H
H
O
H
N
O
R
C
N
R
H
O
C
N
R
H
H
C
N
N-term
R
C
O
N
O
C
N
R
H
R
H
C
N
O
C
O
R
H
N
O
C
O
C-term
R
C
R
R
C
C-term
Secondary Structure
Tertiary Structure
Tertiary Structure
Quaternary Structure
Alcohol dehydrogenase is a homotetramer
The Peptide Plane
Peptide Plane Reduces the Number of Parameters
Tortion angles
 PHI
 PSI
Ramachandran Plot to Evaluate Outliers of “Good Protein Geometry”
Ramachandran plot
from htADH
core (%)
91.3 %
allowed (%)
8.2 %
generously allowed 0.4 %
disallowed
none
Macromolecular Protein Crystallography
Experimental Data Points vs. Refined Parameters
X-ray Diffraction Reflections
Experimental Data Points
Electron Density Map and
Refined Model of Enzyme
RMSD from Ideal Protein Geometry
RMSD from ideal geometry
for htADH structure
bonds (Å)
0.007
angles (°)
1.30
dihedrals (°)
23.60
impropers (°)
0.85
Least Squares Refinement Summed Over all Atoms and Data Points
From Crystallography Made Crystal Clear
Molecular Dynamic Simulation of
a designed mini-protein (Trp-cage)
From the Duan lab
http://www.duanlab.ucdavis.edu/
The movie shown
2 slides ahead is 69.5 MB
and can be downloaded here
Trp Cage Peptide Sequence
1
5
10
15
20
N L Y I Q W L K D G G P S S G R P P P S
HO
1
Q5
Y3
N
D9
L7
O
O
-O
NH2
S13
O
11
G
H2N
H
O
H
N
O
H
N
H3N
H
H
N
N
O
O
H
N
O
H
L
4
I
O
OH
H
O
N
O
H
H
H
O
H
12
P
H
W
H
O
H
N
O
H
S
HN
R16
L2:O
Y3:O
I4:O
W6:H
L7:H
K8:H
G10:O
G11:O
S13:H
S14:H
W6:HE1
R16:O
L7:O
W6:O
G10:H
G11:H
O
OH
+H2N
Hydrogen Bonding Connection
O
N
O
H
P18
14
K8
H
N
O
OH
G10
O
N
N
+H3N
6
P19
O
N
N
O
H
N
N
O
H
N
N
NH
2
H
N
N
O
O
P17
G15
NH2
S20