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.ppthttp://gemdock.life.nctu.edu.tw/dock/download/20100419_spv.pdf

http://ppt.cc/cnqT (ppt)http://ppt.cc/WWxd (pdf)

Contents

Introduction of protein structuresUsing thymidine kinase as an example

Download and installTutorial

Download protein structures from PDBBasic Operation Advance Operation

Resources for tutorialhttp://www.youtube.com/watch?v=yFE3CAHNkZg&feature=related

Introduction of protein structures

Proteins present in all biological organismsPolymers of amino acids (20 L-α-amino acids)

Nanoparticles

Perform particular biochemical functions

Nature:  Mattson, M. Nature. 422, 385-387 (2003)stemcells.nih.go: Early Development

Transcription and translation Cell regulation and catalysis reactions

Introduction of protein structures

To enable to perform protein’s 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

Adapted from Protein Structure in Wikipedia

Hemoglobin: oxy-deoxy states

Adapted from structural biology Wikipedia

Protein structure: from amino acid to quaternary structure

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

Na Cl

Na Cl

Potential energy of Na and Cl Potential energy of Na and Cl

Noncovalent interactions for protein structure and function

van der Waals forceAttractive or repulsive force between molecules

Hydrophobic interactionThe 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 experimentally-determined structures of biological marcomoleculeas (proteins, and DNA/RNA)

Proteins (1kim)

DNAs/RNAs (2k7e)

Biological complexes (1zrc)

X-ray

NMR

EM

http://www.pdb.org/

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

Search result of “X-ray structures of virus’ thymidine kinase with substrates/inhibitors”

TK of virus

TK with ligand (substrate)

PDB ID of this structure

X-ray structure

23 structures for these keywords

Structure and related data (1kim)

The citation of this structure

Related data of this structure

The title of this structure

Visualization of biological assembly

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 PC2. Open the file on a structure

viewer program (swiss PDBviewer, pymol, and etc.)

Classification of Drug Development

Protein

(receptor) S

tructu

re

Compound structure Known Unknown

Known

Unknow

n

Structure-based Drug Design (SBDD)

SBDD or de novo design

High-Throughput Screening(HTS)

Compound similarity searchO

O

O

O

O

O

query Similar compounds

OO

DDT 2002

Discovering new leads

Curr. opin. Chem. Biol. 2002, 439

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

HTSSBDD

• 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.

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 PdbViewerhttp://spdbv.vital-it.ch/download.html

Download user guidehttp://spdbv.vital-it.ch/Swiss-PdbViewerManualv3.7.pdf

Tutorial video (English)http://www.youtube.com/watch?v=nYT5qwtfNew&feature=related

http://www.youtube.com/watch?v=yFE3CAHNkZg

Download page

General Terms

Gray: C atomBlue: N atomRed: O atom

Residue Arginine

Side chain

Main chain

Atom radius

ChainSecondary

Structure (Ribbon)

A protein may have multiple chains

Install and execute swiss pdb viewer

Workspace

Control panel

Layer info

Main window

Viewer

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

1.52A

1 angstrom (A) or 1 × 10−10 meters ?A

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

SheetResidue 50~55

201~207323~328

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 Reisdue Negative ASP

GLUPositive HIS

LYSARG

Polar SERTYRASNTHRGLN

Hydrophobic CYS

METPHEALATRPLEUILEPROVAL

　 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

Secondary Structure

Selected residues

Relative accessibility

default atom colors

Root mean square between 2 molecules

Thymidine kinase

• Function: DNA synthesis

• Therapeutic: Anticancer and antivirus drug target

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

Press left button of mouseto 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 labelPress right button of mouse

1. Q125 recognize the thymine moiety2. 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: 3vtkAnother structure of thymidine kinase

Open layer info

1kim

3vtk

Show or hide

Superimpose two molecules

Results of superimposition

RMS: 0.63 ǺMeasure the structure similarity

Comparison of binding sites-Neighbors of selected residues

Comparison of ligands

HO O

HO

N ONH

O

HO

OO

PO

HO

HO

N

I

ONH

O

1kim: substrate(CPK)3vtk: inhibitor (Green)

Save files

Homework

Keyword1. Capture a picture of N1 neuraminidase (ribbon) and its ligand (stick)

2. Capture a picture of H-bonds between protein and ligand

E-mailpikihsu@gmail.com

Mail title: 學號姓名 _HW2