Introduction to Structural

Bioinformatics

Dong Xu

Computer Science Department271C Life Sciences Center

1201 East Rollins RoadUniversity of Missouri-Columbia

Columbia, MO 65211-2060E-mail: xudong@missouri.edu

573-882-7064 (O)http://digbio.missouri.edu

Structural Bioinformatics

Prediction and modeling

Protein structure

DNA structure

RNA structure

Membrane structures

Large-complex structure

An Overview

o A protein folds into a unique 3D structure under the physiological condition

Lysozyme sequence (129 amino acids):KVFGRCELAA AMKRHGLDNY RGYSLGNWVC AAKFESNFNT QATNRNTDGS

TDYGILQINS RWWCNDGRTP GSRNLCNIPC SALLSSDITA SVNCAKKIVS

DGNGMNAWVA WRNRCKGTDV QAWIRGCRL

Protein backbones: Side chain

Protein Structure Representations

Lysozyme structure:

ball & stick strand surface

[ PDB: http://www.pdb.org ]

Growth of Protein Data Bank (PDB)

Protein Structure Database: PDB (1)

PDB (Protein Data Bank) Web site: http://www.rcsb.org/pdb/ 33,252 Structures as of 25-Oct-2005 PDB ID: 4-character identifier (1cau, 1gox, and 256b) Search methods

* search by PDB ID (e.g. 1lyz);

* SearchLite: protein name, author's name, etc. (e.g., HIV protease);

* SearchFields: EC Number, the name of the binding ligand (e.g.,

inhibitor), the range of the protein size, and the secondary

structure content.

Protein Structure Database: PDB (2)

PDB format (headers + coordinates):

HEADER OXIDOREDUCTASE (OXYGEN(A)) 14-JUN-89 1GOX 1GOX

COMPND GLYCOLATE OXIDASE (E.C.1.1.3.1) 1GOX

...

ATOM 232 N ALA 29 54.035 64.332 19.352 1.00 23.93 1GOX

ATOM 233 CA ALA 29 52.992 65.356 19.569 1.00 24.74 1GOX

ATOM 234 C ALA 29 53.519 66.762 19.309 1.00 25.43 1GOX

ATOM 235 O ALA 29 54.648 67.179 19.655 1.00 25.66 1GOX

ATOM 236 CB ALA 29 52.433 65.340 20.993 1.00 24.54 1GOX

...

HETATM 3165 O HOH 658 62.480 62.480 0.000 0.50 65.79 1GOX

...

END

Molecular Visualization

RasMol: http://www.umass.edu/microbio/rasmol/index2.htm

VMD: http://www.ks.uiuc.edu/Research/vmd

Relevance of Protein Structurein the Post-Genome Era

sequence

structure

function

medicine

Structure-Function Relationship

Certain level of function can be found without structure. But a structure is a key to understand the detailed mechanism.

A predicted structure is a powerful tool for function inference. Trp repressor as a function switch

Structure-Based Drug Design

HIV protease inhibitor

Structure-based rational drug design is still a major method for drug discovery.

Structures in Protein

Language:

Letters Words Sentences

Protein:

Residues Secondary Structure Tertiary Structure

Primary, Secondary and Tertiary Structures of

Proteins

helix

Single protein chain (local) Shape maintained by

intramolecular H bondingbetween -C=O and H-N-

sheet

Several protein chains

Shape maintained byintramolecular H bondingbetween chains

Non-local on protein sequence

-sheet (parallel, anti-parallel)

Dihedral angles

Ramachandran plot (alpha)

Ramachandran plot (beta)

Protein Structure Domain (1)

o Structure domain: compact, globular unit

glycoprotein actin

Protein Structure Domain (2)

o Structure domain is evolutionary, functional, and folding unit of a protein

o Domain insertion: insert: zinc metalloproteinase

+ parent: thioredoxin

(disulfide oxidoreductase)

Dsba: disulfide bond forming protein

o Protein design (growth hormone)o Threading target

Structure Is Better Conserved during

Evolution

Structure can adopt a wide range of mutations.

Physical forces favorcertain structures.

Concept of fold.

Number of fold is limited. Currently ~800 Total: 1,000s ~10,000s TIM barrel

The number of different protein folds is limitedP

DB

sub

mis

sion

s pe

r ye

ar

Year

Already known folds

New folds

Protein Folding Problem

A protein folds into a unique 3D structure under the physiological condition

Lysozyme sequence: KVFGRCELAA AMKRHGLDNY

RGYSLGNWVC AAKFESNFNT

QATNRNTDGS TDYGILQINS

RWWCNDGRTP GSRNLCNIPC

SALLSSDITA SVNCAKKIVS

DGNGMNAWVA WRNRCKGTDV

QAWIRGCRL

Web Addresses

Resource: http://digbio.missouri.edu/resource/

Further reading (a review on protein modeling):

www.bentham.org/cpps1-1/Dong%20Xu/xu_cpps.htm