Introduction to Structural Bioinformatics Dong Xu Computer Science Department 271C Life Sciences Center 1201 East Rollins Road University of Missouri-Columbia Columbia, MO (O)

Structural Bioinformatics l Prediction and modeling l Protein structure l DNA structure l RNA structure l Membrane structures l 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: ] Growth of Protein Data Bank (PDB)

Protein Structure Database: PDB (1) l PDB (Protein Data Bank) Web site: l 33,252 Structures as of 25-Oct-2005 l PDB ID: 4-character identifier (1cau, 1gox, and 256b) l 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 ) 1GOX... ATOM 232 N ALA GOX ATOM 233 CA ALA GOX ATOM 234 C ALA GOX ATOM 235 O ALA GOX ATOM 236 CB ALA GOX... HETATM 3165 O HOH GOX... END

Molecular Visualization RasMol: VMD:

Relevance of Protein Structure in 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 bonding between -C=O and H-N-

 sheet  Several protein chains  Shape maintained by intramolecular H bonding between 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 favor certain 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 limited PDB submissions per year 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:  Further reading (a review on protein modeling):