BCB 444/544
Lecture 20
Protein Structure Basics,
Visualization, Classification & Comparison
#20_Oct08
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
1
Required Reading
(before lecture)
Mon Oct 8 - Lecture 20
Protein Secondary Structure Prediction
• Chp 14 - pp 200 - 213
Wed Oct 10 - Lecture 21
Protein Tertiary Structure Prediction
• Chp 15 - pp 214 - 230
Thurs Oct 11 & Fri Oct 12- Lab 7 & Lecture 22
Protein Tertiary Structure Prediction
• Chp 15 - pp 214 - 230
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
2
BCB 544 - Extra Required Reading
Assigned Mon Sept 24
BCB 544 Extra Required Reading Assignment:
for 544 Extra HW#1 Task 2
• Pollard KS, …., Haussler D. (2006) An RNA gene expressed during
cortical development evolved rapidly in humans. Nature 443: 167-172.
• http://www.nature.com/nature/journal/v443/n7108/abs/nature05113.html
doi:10.1038/nature05113
• PDF available on class website - under Required Reading Link
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
3
BCB 544 Projects (Optional for BCB 444)
• For a better idea about what's involved in the Team
Projects, please look over last year's expectations for
projects: http://www.public.iastate.edu/~f2007.com_s.544/project.htm
Please note: wrong URL (instead of that shown above) was included
in originally posted 544ExtraHW#1; corrected version is posted now
• Criteria for evaluation of projects (oral presentations) are
summarized here:
http://www.public.iastate.edu/%7Ef2007.com_s.544/homework/HW7.pdf
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
4
Assignments & Announcements - #1
Students registered for BCB 444: Two Grading Options
1) Take Final Exam per original Grading Policies
2) Instead of taking Final Exam - you may participate
in a Team Research Project
If you choose #2, please do 3 things:
1) Contact Drena (in person)
2) Send email to Michael Terribilini (terrible@iastate.edu)
3) Complete 544 Extra HW#1 - Task 1.1 by noon on Mon Oct 1
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
5
Assignments & Announcements - #2
BCB 444s (Standard):
200 pts
200
100
500 pts
Midterm Exams = 100 points each
Homework & Laboratory assignments = 200 points
Final Exam
Total for BCB 444
BCB 444p (Project):
200 pts
200
190
590 pts
Midterm Exams = 100 points each
Homework & Laboratory assignments = 200 points
Team Research Project
Total for BCB 444p
BCB 544:
200 pts
200
100
200
700 pts
Midterm Exams = 100 points each
Homework & Laboratory assignments
Final Exam
Discussion Questions & Team Research Projects
Total for BCB 544
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
6
Assignments & Announcements #3
ALL: HomeWork #3
Due: Mon Oct 8 (Today) by 5 PM
• HW544: HW544Extra #1
√Due: Task 1.1 - Mon Oct 1 by noon
Due: Task 1.2 & Task 2 - Fri Oct 12 by 5 PM (not Monday)
• 444 "Project-instead-of-Final" students should also submit:
• HW544Extra #1
• Due: Task 1.1 - Mon Oct 8 (Today) by noon
• Due: Task 1.2 - Fri Oct 12 by 5 PM (not Monday)
Task 2 NOT required!
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
7
Chp 12 - Protein Structure Basics
SECTION V
STRUCTURAL BIOINFORMATICS
Xiong: Chp 12
Protein Structure Basics
•
•
•
•
•
•
•
•
Amino Acids
Peptide Bond Formation
Dihedral Angles
Hierarchy
Secondary Structures
Tertiary Structures
Determination of Protein 3-Dimensional Structure
Protein Structure DataBank (PDB)
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
8
Protein Structure & Function
• Protein structure - primarily determined by sequence
• Protein function - primarily determined by structure
• Globular proteins: compact hydrophobic core & hydrophilic surface
• Membrane proteins: special hydrophobic surfaces
• Folded proteins are only marginally stable
• Some proteins do not assume a stable "fold" until they bind to
something = Intrinsically disordered
 Predicting protein structure and function can be very hard
-- & fun!
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
9
Amino Acids
• Each of 20 different amino acids has different "R-Group" or
side chain attached to Ca
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
10
Peptide Bond is Rigid and Planar
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
11
Certain Side-chain Configurations are
Energetically Favored (Rotamers)
Ramachandran plot:
"Allowable" psi & phi angles
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
12
Glycine is Smallest Amino Acid
R group = H atom
• Glycine residues increase
backbone flexibility because
they have no R group
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
13
Proline is Cyclic
• Proline residues
reduce flexibility of
polypeptide chain
• Proline cis-trans
isomerization is often a
rate-limiting step in
protein folding
• Recent work suggests
it also may also regulate
ligand binding in native
proteins
Andreotti (BBMB)
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
14
Cysteines can Form Disulfide (S-S) Bonds
• Disulfide bonds
(covalent) stabilize
3-D structures
• In eukaryotes,
disulfide bonds are
often found in secreted
proteins or extracellular
domains
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
15
Globular Proteins Have a Compact
Hydrophobic Core
• Packing of hydrophobic side chains into interior is main
driving force for folding
• Problem? Polypeptide backbone is highly polar
(hydrophilic) due to polar -NH and C=O in each
peptide unit (which are charged at neutral pH=7,
found in biological systems); these polar groups must
be neutralized
• Solution? Form regular secondary structures,
• e.g., a-helix, b-sheet- both stabilized by H-bonds
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
16
Exterior Surface of Globular Proteins is
Generally Hydrophilic
• Hydrophobic core formed by packed secondary
structural elements provides compact, stable core
• "Functional groups" of protein are attached to this
framework; exterior has more flexible regions (loops)
and polar/charged residues
• Hydrophobic "patches" on protein surface are often
involved in protein-protein interactions
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
17
Protein Secondary Structures
• aHelices
• bSheets
• Loops
• Coils
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
18
aHelix: Stabilized by H-bonds Between
every ~ 4th Residue in Backbone
C = black
O = red
N = blue
H = white
Look: Charges on backbone are "neutralized"
by hydrogen bonds (H-bonds) - red fuzzy vertical bonds
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
19
Types of aHelices
"Standard" ahelix: 3.6 residues per turn
H-bonds between C=0 of residue n
and N-H of residue n + 4
(this neutralizes backbone chgs)
Helix ends are polar; almost always on surface of protein
Other types of helices?
n + 5 =  helix
n + 3 = 310 helix
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
20
aHelix: R-Groups are on Outside
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
21
Certain Amino Acids are "Preferred" &
Others are Rare in aHelices
• Ala, Glu, Leu, Met = good helix formers
• Pro, Gly Tyr, Ser = very poor
• Amino acid composition & distribution varies,
depending on on location of helix in 3-D structure
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
22
b-Sheets - also Stabilized by H-bonds
Between Backbone Atoms
Anti-parallel
Parallel
b-Sheets: R-Groups are Above & Below "Plane"
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
23
Coils
• Regions of 2' structure that are not helices,
sheets, or recognizable turns
• Intrinsically disordered regions appear to
play important functional roles
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
24
Loops & Turns
• Connect helices and sheets
• Vary in length & 3-D configurations
• Are located on surface of structure
• Are more "tolerant" of mutations
• Are more flexible, can adopt multiple
conformations
• Tend to have charged and polar amino
acids
• Are frequently components of active
sites
• Some fall into distinct structural families
(e.g., hairpin loops, reverse turns)
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
25
Globular Proteins are Built from Recurring
Structural Patterns
• Structural Motifs & supersecondary structures
= combinations of 2' structural elements
• Domains = combinations of motifs
• Independently folding unit (foldon)
• Functional unit
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
26
Simple Motifs Combine to Form Domains
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
27
6 Main Classes of Protein Structure
1) a-Domains
Bundles of helices connected by loops
2) b-Domains
Mainly antiparallel sheets, usually with 2 sheets
forming sandwich
3) abDomains
Mainly parallel sheets with intervening helices,
also mixed sheets
4) abDomains
Mainly segregated helices and sheets
5) Multidomain (a  b
Containing domains from more than one class
6) Membrane & cell-surface proteins
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
28
a-Domain Structures: 4-Helix Bundles
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
29
b-Sheets: Up-and-Down Sheets & Barrels
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
30
ab Domains: Leucine-rich Motifs
can Form Horseshoes
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
31
Protein Structure Databases
PDB - Protein Data Bank
http://www.rcsb.org/pdb/
(RCSB) - THE protein structure database
MMDB - Molecular Modeling Database
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
(NCBI Entrez) - has "added" value
MSD - Molecular Structure Database
http://www.ebi.ac.uk/msd
Especially good for interactions & binding sites
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
32
PDB (RCSB) - recently "remediated"
http://www.rcsb.org/pdb
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
33
Structure at NCBI
http://www.ncbi.nlm.nih.gov/Structure
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
34
MMDB at NCBI
http://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
35
MMDB: Molecular Modeling Data Base
• Derived from PDB structure records
• "Value-added" to PDB records includes:
•
•
•
•
•
•
Integration with other ENTREZ databases & tools
Conversion to parseable ASN.1 data description language
Data also available in mmCIF & XML (also true for PDB now)
Correction of numbering discrepancies in structure vs sequence
Validation
Explicit chemical graph information (covalent bonds)
• Integrated tool for identifying structural neighbors
Vector Alignment Search Tool (VAST)
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
36
MSD: Molecular Structure Database
http://www.ebi.ac.uk/msd/
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
37
wwPDB: World Wide PDB
http://www.wwpdb.org
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
38
Chp 13 - Protein Structure Visualization,
Comparison & Classification
SECTION V
STRUCTURAL BIOINFORMATICS
Xiong: Chp 13
Protein Structure Visualization, Comparison &
Classification
• Protein Structural Visualization
• Protein Structure Comparison
• Protein Structure Classification
BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification
10/8/07
39