Tutorials for protein data bank and swiss PDB viewer

2010/04/19 Prof. Jinn-Moon Yang Yen-Fu Chen and Kai-Cheng Hsu

http://gemdock.life.nctu.edu.tw/dock/download/20100419_spv.ppt http://gemdock.life.nctu.edu.tw/dock/download/20100419_spv.pdf http://ppt.cc/cnqT (ppt) http://ppt.cc/WWxd (pdf)

Contents
Introduction of protein structures
Using thymidine kinase as an example

Download and install Tutorial

Download protein structures from PDB Basic Operation Advance Operation

Resources for tutorial http://www.youtube.com/watch?v=yFE3CAHNkZg&feat ure=related

Introduction of protein structures

Proteins present in all biological organisms
Polymers of amino acids (20 L--amino acids) Nanoparticles Perform particular biochemical functions
Transcription and translation

Cell regulation and catalysis reactions

stemcells.nih.go: Early Development

Nature: Mattson, M. Nature. 422, 385-387 (2003)

Introduction of protein structures

To enable to perform proteins biological function, protein fold into one or more specific spatial conformations driven by noncovalent interactions Hydrogen bonding, ionic interactions, van der Waals forces and hydrophobic packing 3D protein structures are necessary for understanding the functions of protein at molecular level
Protein structure: from amino acid to quaternary structure
Hemoglobin: oxy-deoxy states

Adapted from Protein Structure in Wikipedia

Adapted from structural biology Wikipedia

Noncovalent interactions for protein structure and function

Ionic bond A bond formed by the attraction between two oppositely charged ions Hydrogen bond An attractive interaction of a hydrogen atom with an electronegative atom, like N,O, and F
Potential energy of Na and Cl Potential energy of Na and Cl

Noncovalent interactions for protein structure and function

van der Waals force
Attractive or repulsive force between molecules

Hydrophobic interaction
The physical property of a molecule (known as a hydrophobe) that is repelled from a mass of water
An example of van der Waals force: Gecko climbs on the glass An example of hydrophobic interaction: Water drops on hydrophobic surface

Protein structure database: Protein data bank (PDB)

Techniques for determining atomic structures X-ray crystallography, NMR spectroscopy and electron microscopy PDB contains information about experimentallydetermined structures of biological marcomoleculeas (proteins, and DNA/RNA)
Proteins (1kim)
X-ray

NMR

DNAs/RNAs (2k7e)
EM

http://www.pdb.org/

Biological complexes (1zrc)

Search protein structures in PDB

PDB provides search by protein name, ligand, or structrue related keywords Search example: thymidine kinase (TK)

Function: DNA synthesis Therapeutic: Anticancer and antivirus drug target

Example: X-ray structures of virus thymidine kinase with substrates/inhibitors

Protein name Source spices

Experimental method has ligands

thymidine kinase with substrates/inhibitors

23 structures for these keywords

Search result of X-ray structures of virus

PDB ID of this structure

TK of virus TK with ligand (substrate) X-ray structure

Structure and related data (1kim)

Related data of this structure The title of this structure Visualization of biological assembly

The citation of this structure

Structure and ligand data (1kim)

Ligand in this structure

Structure and sequence data (1kim)

Related data of this structure

Sequence ID of 1kim in UniProtKB Structure classification ID of 1kim

Advance inspection for protein structure: download structure from PDB

1. Save the data on your PC 2. Open the file on a structure viewer program (swiss PDBviewer, pymol, and etc.)

Classification of Drug Development

Protein (receptor) Structure
Compound similarity search
O O O O

High-Throughput Screening (HTS)

Unknown Known
O

query

Similar compounds SBDD or de novo design

Structure-based Drug Design (SBDD)

O

Known

DDT 2002 Unknown

Compound structure

Discovering new leads

SBDD HTS

Yellow: virtual screening (SBDD) Blue: high-throughput screening (HTS)

There are more than 5 H-bond donors. The molecular weight is over 500. The LogP is over 5. There are more than 10 H-bond acceptors.

Curr. opin. Chem. Biol. 2002, 439

Drugs derived from structure-based approaches

Drug Discovery Today, 10, 895, 2005

Drug Discovery Today, 10, 895, 2005

Tutorial for Swiss PDB viewer

Download and install

Download Swiss PdbViewer
http://spdbv.vital-it.ch/download.html

Download user guide

http://spdbv.vital-it.ch/SwissPdbViewerManualv3.7.pdf

Tutorial video (English)

http://www.youtube.com/watch?v=nYT5qwtfNew&fe ature=related http://www.youtube.com/watch?v=yFE3CAHNkZg

Download page

General Terms
Main chain Residue Arginine Chain Secondary Structure (Ribbon)

Side chain
Gray: C atom Blue: N atom Red: O atom Atom radius

A protein may have multiple chains

Install and execute swiss pdb viewer

Workspace
Layer info Main window Viewer

Control panel

Move & Rotate

Center Zoom

Translate

Rotate

Open control panel

control panel

Load PDB1

Load PDB2

Display or hide residues -for some residues

Press left button of mouse

Display or hide residues -for all residues

Press right button of mouse

Display or hide side chains of residues

Display or hide residue labels

GLU111

Display or hide atom radius

Render in solid 3D

Show secondary structures -Display or hide ribbons

Bond length

1 angstrom (A) or 1 1010 meters

?A

1.52A

Bond length

?A

Bond length

Hydrogen bond length

?A

Hydrogen bonds of helix

Hydrogen bond of helix

Hydrogen bonds of helix

Helix

Hydrogen bonds of sheet

Sheet Residue 50~55 201~207 323~328

Number of helix ? From residue 46~146

Change color

Visualization of biological assembly -color by chain

Change color by chain -act on Ribbons

Show residue properties -Change color by Type

Type Negative Positive Reisdue ASP GLU HIS LYS ARG SER TYR ASN THR GLN CYS

Polar

Hydrophobic

MET PHE ALA TRP LEU ILE PRO VAL GLY

Show structure flexibility Change color by B-factor

A low B-factor meaning that the position of the atom has been determined with accuracy

High B-factor

Low B-factor

Other color types

default atom colors

Root mean square between 2 molecules

Secondary Structure

Selected residues

Relative accessibility

Thymidine kinase

Function: DNA synthesis Therapeutic: Anticancer and antivirus drug target

Analyze protein-ligand interactions -Select ligands (or residues)

Press left button of mouse to select the ligand (THM, thymidine) of 1kim

Identify binding site -Show protein (ribbon) and ligand (stick)

Select residues in the binding site -Neighbors of selected residues

Center selected residues

H-bonds of the binding site -Compute H-bonds

H-bonds between protein and ligand -Show H-bonds of selection

H-bonds between TK and THM -Show residues from selection

Show residue label

Press right button of mouse

1. Q125 recognize the thymine moiety 2. Activity was decreased by over 90% if Q125 mutated (Biochemistry, 2000.
39: p. 4105-4111)

van der Waal forces -Stacking interactions

M128 and Y172 sandwich the thymine moiety Stabilize the binding of substrate (JBC, 1999. 274: p. 31967-31973)

Observe the protein surface -Compute Surface

Surface preference

Show ligand in the surface

Discard surface

Comparison of multiple structures -Import PDB

PDB code: 3vtk Another structure of thymidine kinase

Open layer info

Show or hide

1kim

3vtk

Superimpose two molecules

Results of superimposition

RMS: 0.63 Measure the structure similarity

Comparison of binding sites -Neighbors of selected residues

Comparison of ligands

3vtk: inhibitor (Green)

1kim: substrate(CPK)

Save files

Homework
Keyword
1. Capture a picture of N1 neuraminidase (ribbon) and its ligand (stick) 2. Capture a picture of H-bonds between protein and ligand

E-mail
pikihsu@gmail.com Mail title: _HW2