10/8/07bcb 444/544 f07 isu dobbs #20 - protein structure basics & classification1 bcb 444/544...

10/8/07BCB 444/544 F07 ISU Dobbs #20 - Protein Structure Basics & Classification 1

BCB 444/544

Lecture 20

Protein Structure Basics,Visualization, Classification &

Comparison

#20_Oct08


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

Required Reading (before lecture)


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 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

• Criteria for evaluation of projects (oral presentations) are summarized here: http://www.public.iastate.edu/%7Ef2007.com_s.544/homework/

HW7.pdf

Please note: wrong URL (instead of that shown above) was includedin originally posted 544ExtraHW#1; corrected version is posted now


Assignments & Announcements - #1

Students registered for BCB 444: Two Grading Options

1) Take Final Exam per original Grading Policies2) Instead of taking Final Exam - you may

participate in a Team Research Project

If you choose #2, please do 3 things:• Contact Drena (in person) • Send email to Michael Terribilini ([email protected])• Complete 544 Extra HW#1 - Task 1.1 by noon on Mon

Oct 1


Assignments & Announcements - #2

BCB 444s (Standard):200 pts Midterm Exams = 100 points each 200 Homework & Laboratory assignments = 200 points100 Final Exam500 pts Total for BCB 444

BCB 444p (Project):

200 pts Midterm Exams = 100 points each 200 Homework & Laboratory assignments = 200 points190 Team Research Project590 pts Total for BCB 444p

BCB 544: 200 pts Midterm Exams = 100 points each 200 Homework & Laboratory assignments100 Final Exam 200 Discussion Questions & Team Research Projects 700 pts Total for BCB 544


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!


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)


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!


Amino Acids

• Each of 20 different amino acids has different "R-Group" or side chain attached to C


Peptide Bond is Rigid and Planar


Certain Side-chain Configurations are Energetically Favored (Rotamers)

Ramachandran plot: "Allowable" psi & phi angles


Glycine is Smallest Amino AcidR group = H atom

• Glycine residues increase backbone flexibility because they have no R group


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)


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


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., -helix, -sheet- both stabilized by H-bonds


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


Protein Secondary Structures

• Helices

• Sheets

• Loops

• Coils


Helix: Stabilized by H-bonds Between

every ~ 4th Residue in Backbone

C = blackO = redN = blueH = white

Look: Charges on backbone are "neutralized" by hydrogen bonds (H-bonds) - red fuzzy vertical

bonds


Types of Helices

"Standard" 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


Helix: R-Groups are on Outside


Certain Amino Acids are "Preferred" & Others are Rare in 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


-Sheets - also Stabilized by H-bonds Between Backbone Atoms

Anti-parallel Parallel

-Sheets: R-Groups are Above & Below "Plane"


Coils

• Regions of 2' structure that are not helices, sheets, or recognizable turns

• Intrinsically disordered regions appear to play important functional roles


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)


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


Simple Motifs Combine to Form Domains


6 Main Classes of Protein Structure

1) -Domains

Bundles of helices connected by loops2) -Domains

Mainly antiparallel sheets, usually with 2 sheets forming sandwich

3) DomainsMainly parallel sheets with intervening

helices, also mixed sheets4) Domains

Mainly segregated helices and sheets

5) Multidomain (Containing domains from more than one class

6) Membrane & cell-surface proteins


-Domain Structures: 4-Helix Bundles


-Sheets: Up-and-Down Sheets & Barrels


Domains: Leucine-rich Motifs can Form Horseshoes


Protein Structure Databases

PDB - Protein Data Bank http://www.rcsb.org/pdb/

(RCSB) - THE protein structure database

MMDB - Molecular Modeling Databasehttp://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


PDB (RCSB) - recently "remediated" http://www.rcsb.org/pdb


Structure at NCBIhttp://www.ncbi.nlm.nih.gov/Structure


MMDB at NCBI http://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml


MMDB: MMolecular MModeling 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)


MSD: MMolecular SStructuretructure Database

http://www.ebi.ac.uk/msd/


wwPDB: World Wide PDBhttp://www.wwpdb.org


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

10/8/07bcb 444/544 f07 isu dobbs #20 - protein structure basics & classification1 bcb 444/544...

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