Protein Structure Protein Structure BasicsBasics

Presented byPresented by

Alison Fraser, Christine Lee, Alison Fraser, Christine Lee, PradhumanPradhuman JhalaJhala, , CorbanCorban RiveraRivera

Importance of ProteinsImportance of Proteins

Muscle structure depends on proteinMuscle structure depends on protein--protein protein interactionsinteractionsTransport across membranes involves proteinTransport across membranes involves protein--solute interactionssolute interactionsNerve activity requires transmitter substanceNerve activity requires transmitter substance--protein interactionsprotein interactionsImmune protection requires antibodyImmune protection requires antibody--antigen antigen interactionsinteractions

OverviewOverview

Primary StructurePrimary StructureSecondary StructureSecondary StructureTertiary StructureTertiary StructureQuaternary StructureQuaternary Structure

Primary StructurePrimary Structure

Polypeptide chains Polypeptide chains Amino Amino AcidsAcidsLargest polypeptide chain Largest polypeptide chain approx has 5000AA but most approx has 5000AA but most have less than 2000AAhave less than 2000AAAmino Acid Basic Structure Amino Acid Basic Structure HH22NN--CHCH--COOHCOOHArrangement of the 20 Arrangement of the 20 amino acids in the amino acids in the polypeptide is the amino acid polypeptide is the amino acid sequence which composes sequence which composes the primary structure of the the primary structure of the proteinprotein

National Genome Research Institutegenome.gov

http://www.people.virginia.edu/~rjh9u/aminacid.html

20 Amino Acids

Nonpolar,hydrophobic

Polar, uncharged

Polar, charged

Amino Acid ClassificationAmino Acid Classification

Bioinformatics Methods II, Spring 2003

HK R

ED

F YW

IL V

M

A

Q

S N

T

CH

G PCS-S

polar

positive

negative

charged

beta-branched

aliphatic

aromatic

hydrophobic

A Venn diagram showing the relationship of the 20 naturally occurring amino acids to a selection of physio-chemical properties thought to be important in the determination of protein structure.

StereochemistryStereochemistry

Configuration of amino acids in proteinsConfiguration of amino acids in proteinsThe CORN LawThe CORN Law

Bond FormationBond Formation

Linking two amino acids Linking two amino acids togethertogether

Definitions (NDefinitions (N--terminal, terminal, CC--terminal, polypeptide terminal, polypeptide backbone, amino acid backbone, amino acid residue, side chains)residue, side chains)

http://web.mit.edu/esgbio/www/lm/proteins/peptidebond.html

Primary StructurePrimary Structure

What is a native protein?What is a native protein?Protein conformation & problem of protein Protein conformation & problem of protein foldingfolding

Hydrophobic, hydrophilicHydrophobic, hydrophilicChargeChargeChaperonesChaperones

Special Purpose Amino AcidsSpecial Purpose Amino Acids

ProlineProline

CysteineCysteine

IntroductionIntroductionPeptide bond geometryPeptide bond geometryRamachandranRamachandran plotplotStructuresStructures

Protein Secondary StructureProtein Secondary Structure

Regular local structures formed by single strands Regular local structures formed by single strands of peptide chain due to constraints on backbone of peptide chain due to constraints on backbone conformationconformation

Peptide BondPeptide Bond

http://cmgm.stanford.edu/biochem/biochem201/Slides/

Peptide Bond Peptide Bond

Resonance Resonance CC--N bond length of the peptide is 10% shorter N bond length of the peptide is 10% shorter than that found in usual Cthan that found in usual C--N amine bondsN amine bondsPeptide bond planer Peptide bond planer ωω, angle around peptide bond, , angle around peptide bond, 0000 for for ciscis, 180, 18000 for transfor trans

RamachandranRamachandran PlotPlot

http://hykim.chungbuk.ac.kr/lectures/biochem/4-5/fig6-9(L).jpg

Alpha HelixAlpha Helix

http://cmgm.stanford.edu/biochem/biochem201/Slides/

Alpha HelixAlpha Helix

LeftLeft--handedhanded RightRight--handedhanded

http://www.rtc.riken.go.jp

Alpha Structure FeaturesAlpha Structure Features

3.6 residues per turn3.6 residues per turn5.4 angstroms in length per turn5.4 angstroms in length per turncarboxyl group of residue i hydrogen bonds to carboxyl group of residue i hydrogen bonds to amino group of residue i+4amino group of residue i+4

Helix StructuresHelix Structures

Φ ψ H Bond R/t A/tΦ ψ H Bond R/t A/tAlpha Alpha --57.8 57.8 --47 i, i + 4 3.6 1347 i, i + 4 3.6 13

33--10 Helix 10 Helix --49 49 --26 i, i + 3 3.0 1026 i, i + 3 3.0 10

Pi Helix Pi Helix --57 57 --80 i , i + 5 4.4 1680 i , i + 5 4.4 16

http://broccoli.mfn.ki.se

More Helix StructuresMore Helix Structures

TypeType ΦΦ ψψ commentscomments

CollagenCollagen --5151 153153 Fibrous proteinsFibrous proteinsThree left handed Three left handed helicieshelicies((GlyXY)nGlyXY)n, X Y = Pro / , X Y = Pro / LysLys

Type II helicesType II helices --7979 150150 leftleft--handed handed helicieshelicies formed formed by by polyglycinepolyglycine

Beta Sheet Beta Sheet

http://www.rothamsted.bbsrc.ac.uk/notebook/courses/guide/images/sheet.gif

Beta Sheet FeaturesBeta Sheet Features

Sheets can be made up of any number of strandsSheets can be made up of any number of strandsOrientation and hydrogen bonding pattern of Orientation and hydrogen bonding pattern of strands gives rise to flat or twisted sheetsstrands gives rise to flat or twisted sheetsParallel sheets buried inside, while Parallel sheets buried inside, while AntiparallelAntiparallelsheets occurs on the surfacesheets occurs on the surface

More Beta StructuresMore Beta Structures

Beta Bulge chymotrypsin (1CHG.PDB) involving residues 33 and 41-42

Anti parallel

Beta Twist pancreatic trypsin inhibitor (5PTI)0 to 30 degrees per residue

Distortion of tetrahedral N atom

http://broccoli.mfn.ki.se

Beta turnsBeta turns

i + 1 Pro

i + 2 Pro or Gly

i + 3 Gly

http://rayl0.bio.uci.edu/~mjhsieh/sstour/image/betaturn.png

Interactions Interactions

Covalent bondsCovalent bondsDisulphide bond (2.2 Disulphide bond (2.2 00A) between two A) between two CysCys residuesresidues

NonNon--covalent bondscovalent bondsLong range electrostatic interactionLong range electrostatic interactionShort range (4 Short range (4 00A) van A) van derder WaalsWaals interactioninteractionHydrogen bond (3 Hydrogen bond (3 00A)A)

Tertiary Protein StructureTertiary Protein Structure

Defines the three dimensional conformation of Defines the three dimensional conformation of an entire peptide chain in spacean entire peptide chain in spaceDetermined by the primary structureDetermined by the primary structureModular in natureModular in nature

Aspects which determine tertiary Aspects which determine tertiary structurestructure

Covalent disulfide bonds from between closely Covalent disulfide bonds from between closely aligned aligned cysteinecysteine residues form the unique Amino residues form the unique Amino Acid Acid cystinecystine..Nearly all of the polar, hydrophilic R groups are Nearly all of the polar, hydrophilic R groups are located in the surface, where they may interact located in the surface, where they may interact with waterwith waterThe The nonpolarnonpolar, , hydropobichydropobic R groups are usually R groups are usually located inside the moleculelocated inside the molecule

Motifs and DomainsMotifs and Domains

Motif Motif –– a small structural domain that can be a small structural domain that can be recognized in a variety of proteinsrecognized in a variety of proteinsDomain Domain –– Portion of a protein that has a tertiary Portion of a protein that has a tertiary structure of its own. In larger proteins each structure of its own. In larger proteins each domain is connected to other domains by short domain is connected to other domains by short flexible regions of polypeptide. flexible regions of polypeptide.

Modular Nature of Modular Nature of ProtiensProtiens

Epidermal Growth Epidermal Growth Factor (EGF) domain is Factor (EGF) domain is a module present in a module present in several different proteins several different proteins illustrated here in orange.illustrated here in orange.Each color represents a Each color represents a different domaindifferent domain

Domain ShufflingDomain Shuffling

Occurs in evolutionOccurs in evolutionNew proteins arise by joining of New proteins arise by joining of preexistingpreexistingprotein domain or modules.protein domain or modules.

Quaternary StructureQuaternary Structure

Not all proteins have a Not all proteins have a quaternary structurequaternary structureA composite of multiple A composite of multiple polypoly--peptide chains is peptide chains is called an called an oligomeroligomer or or multimericmultimericHemoglobin is an Hemoglobin is an example of a tetramerexample of a tetramerGlobular vs. FibrousGlobular vs. Fibrous

Protein FoldingProtein Folding

Protein folding constitutes the process by which Protein folding constitutes the process by which a polya poly--peptide chain reduces its free energy by peptide chain reduces its free energy by taking a secondary, tertiary, and possibly a taking a secondary, tertiary, and possibly a quaternary structurequaternary structure

ThermodynamicsThermodynamics

Proteins follow Proteins follow spontaneous reactions to spontaneous reactions to reach the conformation reach the conformation of lowest free energyof lowest free energyReaction spontaneity is Reaction spontaneity is modeled by the equation modeled by the equation ∆∆G= G= ∆∆HH--TT∆∆S S

Molecular VisualizationMolecular Visualization

Goal: Clear visualization of Goal: Clear visualization of molecular structuremolecular structureDifferent visualization modes Different visualization modes elucidate different molecular elucidate different molecular propertiespropertiesSome representations include Some representations include Ribbons, Ribbons, SpaceFillSpaceFill and and BackboneBackbone