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Principles of Protein Structure . PHAR 201/Bioinformatics I Philip E. Bourne School of Pharmacy & Pharm. Sci., UCSD Prerequisite Reading: Structural Bioinformatics Chapters 1-2 Thanks to Eric Scheeff and Lynn Fink. Remember .

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principles of protein structure

Principles of Protein Structure

PHAR 201/Bioinformatics I

Philip E. Bourne

School of Pharmacy & Pharm. Sci., UCSD

Prerequisite Reading: Structural Bioinformatics Chapters 1-2

Thanks to Eric Scheeff and Lynn Fink

PHAR201 Lecture 1 2012

remember
Remember ..
  • The first 2 lectures are not so much to teach/refresh your knowledge of protein/DNA/RNA structure, but for you to conceptualize, describe and subsequently analyze complex biological data
  • Assignment 1 will test this

PHAR201 Lecture 1 2012

remember1
Remember..
  • All which we study is an abstraction to make comprehension of a complex entity more straightforward
  • We think of structures as static entities, but they are dynamic, sometimes to the point of being ill-definable – function requires this flexibility
  • The more we have the more we should know and use – contrast Kendrew to the PDB today

PHAR201 Lecture 1 2012

primary structure amino acids
Primary Structure - Amino Acids
  • It is the amino acid sequence (1940) that “exclusively” determines the 3D structure of a protein
  • 20 amino acids – modifications do occur post translationally

PHAR201 Lecture 1 2012

amino acids continued
Amino Acids Continued…
  • It is the properties of the R group that determine the property of the aa and ultimately the protein
  • Different schemes exist for describing the properties Willie Taylor’s scheme is often employed in bioinformatics analyses
  • Hydrophobicity, polarity and charge are common measures
  • Learn the amino acid codes, structures and properties!

PHAR201 Lecture 1 2012

Primary Structure

amino acids continued1
Amino Acids Continued…
  • Chirality – amino acids are enatiomorphs, that is mirror images exist – only the L(S) form is found in naturally forming proteins. Some enzymes can produce D(R) amino acids
  • Think about a data structure for this information – annotation and a validation procedure should be included
  • Think about systematic versus common nomenclature

PHAR201 Lecture 1 2012

Primary Structure

peptide bond formation
Peptide Bond Formation
  • Individual amino acids form a polypeptide chain
  • Such a chain is a component of a hierarchy for describing macromolecular structure
  • The chain has its own set of attributes
  • The peptide linkage is planar and rigid

PHAR201 Lecture 1 2012

Primary Structure

geometry of the chain
Geometry of the Chain
  • A dihedral angle is the angle between two planes defined by 4 atoms – 123 make one plane; 234 the other
  • Omega is the rotation around the peptide bond Cn – Nn+1 – it is planar and is 180 under ideal conditions
  • Phi is the angle around N – Calpha
  • Psi is the angle around Calpha C’
  • The values of phi and psi are constrained to certain values based on steric clashes of the R group. Thus these values show characteristic patterns as defined by the Ramachandran plot

PHAR201 Lecture 1 2012

From Brandon and Tooze

Secondary Structure

ramachandran plot
Ramachandran Plot
  • Shows allowed and disallowed regions
  • Gly and Pro are exceptions: Gly has no limitation; Pro is constrained by the fact its side chain binds back to the main chain

Gray = allowed conformations. βA, antiparallel b sheet; βP, parallel b sheet; βT, twisted b sheet (parallel or anti-parallel); α, right-handed α helix; L, left-handed helix; 3, 310 helix; p, Π helix.

PHAR201 Lecture 1 2012

Secondary Structure

secondary structure
Secondary Structure
  • The chemical nature of the carboxyl and amino groups of all amino acids permit hydrogen bond formation (stability) and hence defines secondary structures within the protein.
  • The R group has an impact on the likelihood of secondary structure formation (proline is an extreme case)
  • This leads to a propensity for amino acids to exist in a particular secondary structure conformation
  • Helices and sheets are the regular secondary structures, but irregular secondary structures exist and can be critical for biological function

PHAR201 Lecture 1 2012

Secondary Structure

alpha helix
Alpha Helix
  • A helix can turn right or left from N to C terminus – only right-handed are observed in nature as this produces less clashes
  • All hydrogen bonds are satisfied except at the ends = stable

PHAR201 Lecture 1 2012

Secondary Structure

alpha helix continued
Alpha Helix Continued
  • There are 3.6 residues per turn
  • A helical wheel will outline the surface properties of the helix

PHAR201 Lecture 1 2012

Secondary Structure

other rarer helix types 3 10
Other (Rarer) Helix Types - 310
  • Less favorable geometry
  • 3 residues per turn with i+3 not i+4
  • Hence narrower and more elongated
  • Usually seen at the end of an alpha helix

PHAR201 Lecture 1 2012

4HHB

Secondary Structure

other very rare helix types
Other (Very Rare) Helix Types - Π
  • Less favorable geometry
  • 4 residues per turn with i+5 not i+4
  • Squat and constrained

PHAR201 Lecture 1 2012

Secondary Structure

beta sheets
Beta Sheets

PHAR201 Lecture 1 2012

Secondary Structure

beta sheets continued
Beta Sheets Continued
  • Between adjacent polypeptide chains
  • Phi and psi are rotated approximately 180 degrees from each other
  • Mixed sheets are less common
  • Viewed end on the sheet has a right handed twist that may fold back upon itself leading to a barrel shape (a beta barrel)
  • Beta bulge is a variant; residue on one strand forms two hydrogen bonds with residue on other – causes one strand to bulge – occurs most frequently in parallel sheets

PHAR201 Lecture 1 2012

Secondary Structure

other secondary structures loop or coil
Other Secondary Structures – Loop or Coil
  • Often functionally significant
  • Different types
    • Hairpin loops (aka reverse turns) – often between anti-parallel beta strands
    • Omega loops – beginning and end close (6-16 residues)
    • Extended loops – more than 16 residues

1AKK

PHAR201 Lecture 1 2012

Secondary Structure

tertiary structure
Tertiary Structure
  • Myoglobin (Kendrew 1958) and hemoglobin (Perutz 1960) gave us the proven experimental insights into tertiary structure as secondary structures interacting by a variety of mechanisms
  • While backbone interactions define most of the secondary structure interactions, it is the side chains that define the tertiary interactions

PHAR201 Lecture 1 2012

Tertiary Structure

components of tertiary structure
Components of Tertiary Structure
  • Fold – used differently in different contexts – most broadly a reproducible and recognizable 3 dimensional arrangement
  • Domain – a compact and self folding component of the protein that usually represents a discreet structural and functional unit
  • Motif (aka supersecondary structure) a recognizable subcomponent of the fold – several motifs usually comprise a domain

Like all fields these terms are not used strictly making capturing data that conforms to these terms all the more difficult

PHAR201 Lecture 1 2012

Tertiary Structure

tertiary structure as dictated by the environment
Tertiary Structure as Dictated by the Environment
  • Proteins exist in an aqueous environment where hydrophilic residues tend to group at the surface and hydrophobic residues form the core – but the backbone of all residues is somewhat hydrophilic – therefore it is important to have this neutralized by satisfying all hydrogen bonds as is achieved in the formation of secondary structures
  • Polar residues must be satisfied in the same way – on occasion pockets of water (discreet from the solvent) exist as an intrinsic part of the protein to satisfy this need
  • Ion pairs (aka salt bridge) form important interactions
  • Disulphide linkages between cysteines form the strongest (ie covalent tertiary linkages); the majority of cysteines do not form such linkages

5EBX

PHAR201 Lecture 1 2012

Tertiary Structure

tertiary structure as dictated by protein modification
Tertiary Structure as Dictated by Protein Modification
  • To the amino acid itself eg hydroxyproline needed for collagen formation
  • Addition of carbohydrates (intracellular localization)
  • Addition of lipids (binding to the membrane)
  • Association with small molecules – notably metals eg hemoglobin

PHAR201 Lecture 1 2012

Tertiary Structure

there are different forms of classification apart from structural
There are Different Forms of Classification apart from Structural
  • Biochemical
    • Globular
    • Membrane
    • Fibrous

myoglobin

Bacteriorhodopsin

Collagen

PHAR201 Lecture 1 2012

quaternary structure
Quaternary Structure
  • The biological function of some molecules is determined by multiple polypeptide chains – multimeric proteins
  • Chains can be identical eg homeodimer or different eg heterodimer
  • The interactions within multimers is the same as that found in tertiary and secondary structures

PHAR201 Lecture 1 2012

slide24

Hemoglobin:

Enhanced binding

capability of oxygen

Cooperativity

Glutamine sythetase:

Controlled use of

Nitrogen from

Multiple active sites

Co-location of

Function

Combination

Immunoglobulin:

Multiple receptor

responses

Structural

Assembly

Actin:

Giving the cell shape

and form

PHAR201 Lecture 1 2012

Quaternary Structure

quaternary structure ferritin the bodies iron storage protein
Quaternary Structure: Ferritin - The Bodies Iron Storage Protein

PHAR201 Lecture 1 2012

Quaternary Structure

disorder
Disorder?

PHAR201 Lecture 1 2012

additional reading
Additional Reading
  • Branden and Tooze (1999) Introduction to Protein Structure (2nd Edition) Garland Publishing.

An excellent introduction

  • Richardson (1981) The Anatomy and Taxonomy of Protein Structure Adv. Protein Chem. 34: 167-339

Good historical perspective

PHAR201 Lecture 1 2012

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