the main moe windows

The Main MOE Windows

SVL Commands Window (CLI)

Custom SVL, interactive scripting, session logging

Sequence Editor (SE)Protein bioinformatics, homology modeling, sequence analysis

MOE Database Viewer (DBV)

Cheminformatics, conformational search, fingerprints, clustering, combinatorial library design

The MOE Window(MOE) or ( )Small molecule bioinformatics, Molecular mechanics, Small molecule visualization, Forcefield applications

Intro 1: The MOE WindowUsed for:

• Building small molecules

• Molecular mechanics

• Structure-based drug design

• Docking

• SCF Calculations

• Molecular dynamics

• Flexible alignment

• PH4 elucidation

• Conformational searching

Intro 2: The Sequence EditorUsed for:

• Protein bioinformatics

• Sequence alignment

• Homology searching

• Homology modeling

• Target family analysis

• RCSB download

• Consensus modeling

• PDB searching

Intro 3: The MOE Database Viewer

Used for:

• Cheminformatics• QSAR• Conformation search output• Dynamics output• Flexible alignment output• Docking output• Clustering• Fingerprints• Similarity search• Diverse subset• Data correlation• Combinatorial library design• R-group preparation• PH4 searching• Washing / Preprocessing

Intro 4: The SVL Commands Window

Used for:

• Custom SVL

• Interactive scripting

• Session logging

Layout of Course

1. Main MOE Window:

a) Opening/saving files

b) Building molecules

c) Rendering

2. Introduction to the Sequence Editor

3. Introduction to the Database Viewer

a) Basics of molecular mechanics and conformational searching

b) Basics of cheminformatic analysis with the Database Viewer

4. Comments on SVL

1. Structure of the MOE WindowMain Menu Commands

SVL Command Line

3D Rendering Area

Task Cancel Button

RHS ButtonBar

Footer Pager Bar

Popup menu

Mouse Conventions in MOE

General Mouse Actions 3-Button Mouse –

2-Button Mouse MappingLEFT

- Selecting objects, menu commands

MIDDLE

- Rotating, translating moving objects

RIGHT

- SE and DBV Popup menus

<Alt>Press and release key

Input / Output File Formats in MOE

• MOE can read various input formats, e.g. MOE, PDB, SD etc.

• A variety of export file formats are possible, e.g. MOE, Tripos MOL2 etc.

• Picture files may be generated for publications or presentations.

Opening Files in MOE – (File | Open)

Recent Directories

List

Operations to Perform on selected file(s)

Enforce File Type

Change Working Directory (CWD)

Current Path/ Directory

Open file in text editorOpen file

into MOE

Directory/ File List

Path Text Field

‘..’ go up a

Directory

Exercise: Opening a File

3. Find the file $MOE/sample/mol/sulph_quin.moe

4. Open MOE file into the MOE Window by either:

a) Selecting the file and clicking OK or Open in MOE.

b) Double left-clicking on the filename.

1. Open the File Open panel (File | Open).

2. Use the pull-down menu to switch to the $MOE/sample/mol directory.

Exercise: Opening a File (cont.)

5. Center the View (Render | View or RHS | View).

6. Render the molecule in stick mode (Render | Stick).

Exercise: Manipulate molecule in 3D Window

Left Click:Select atoms one at a time

Middle Drag:

XY Rotate

Left Drag:

Selection Box

Ctrl Middle Drag or Scroll wheel

Zoom in/out

Right Click:

Popup menu

Middle click:Change center of rotation

Left Click in Empty Space:To de-select to clear

Exercise: Saving a picture (1)

3. Click on Set CWD to set as the new working directory

2. Click on MkDir to create a new directory called ‘course’

1. Choose MOE | File | Save

Exercise: Saving a picture (2)

4. Choose Save ‘Picture’ 5. Enter the filename ‘sulph_quin.png’

6. Choose Format ‘PNG’

7. Finally click on Save

Rendering 2D Depicted Molecules

1. MOE | Edit | Automatic | Depict as 2D

2. Press ‘Export Bitmap’ to save picture as ‘sulph_quin2.png’

3. Press OK

4. Press Close

• Create Molecular Surfaces via the Molecular Surface panel

(MOE | Compute | Surfaces and Maps)

• Manage surfaces and other graphics objects with the Graphic Object Manager

(MOE | Window | Graphic Objects)

Drawing Molecular Surfaces

Molecular Surfaces and Maps

• Tool for active site analysis

– Integration of three applications:Molecular Surfaces, Contact Preference Maps and new Electrostatic Maps

– Easy control of definition for atom sets

– Automatic handling of surface names for easy comparisons

• Build molecular surfaces

– Gaussian, Connolly and VDW

– Color by various properties

• Predict contact preferences

– Plot knowledge based potentials for hydrophilic and hydrophobic contacts

• Calculate electrostatic maps

– Plot electrostatically preferred positive, negative and neutral regions

Exercise: Drawing Molecular Surfaces (1)

1. Draw a surface around the inhibitor by first choosing (MOE | Compute | Surfaces and Maps) using the default options

2. Press Apply

To print the current MOE 3D window choose MOE | File | Print...

Printer or Postscript file

Header

Landscape/Portrait

Footer

Exercise: Outputting the system… to the printer

Exercise: Outputting the system… to various formats

1. Save the current MOE 3D window. MOE | File | Save...

2. Enter filename to save ‘my_sulph_quin.moe’

3. Choose Save: Molecule and Format: .moe. To save surface, select Graphics:All

4. Click on Save

Exercise: Close System and Open Builder

1. Close the current system

(MOE | RHS | Close)

2. Open the Builder

(MOE | RHS | Builder)

The Molecule Builder

Edit or Add Element

Enter Fragment SMILES string

Edit:1. Compound Name2. Bond Length3. Bond Angle4. Torsion

Edit Ionization State

Fragment substitution buttons

Other atom types, including dummy atom at centroid

Edit Chirality

Library of functional groups

Undo button

Exercise: Build a molecule

Select C

Press

Press

Select C Press

Shift-select 2 C Press

Shift-select 2 C Press

<Shift>

<Shift>

Exercise: Build a molecule (cont.)

Select H Press

Press 4 times


Select H

Press


Press

Select H

Press

Deselect H

Exercise: Energy Minimize

RHS | Minimize

Save Molecule

1. Save the current MOE 3D window as a MOE file.

MOE | File | Save...

Enter filename to save ‘my_first_molecule.moe’

Save ‘Molecule’

Choose Format ‘MOE’

2. Press Save

Selecting Atoms with the Left Mouse Button

Left Drag:

Selection Box

<Ctrl>-Left Click:Auto-extend selection to residue

<Shift>-Left Click:Add to / toggle atom selection

<Ctrl>

<Shift>

Left Click:Select atoms one at a time

Note on <Ctrl>-Left Click:There is only one residue in the built molecule, so the whole molecule will be selected. This will be revisited later.

Exercise: Selecting Atoms with the Left Mouse Button

1. Use Left-Click to select atoms one at a time.

2. Use Left-Drag to draw a selection box.

3. Use <Shift>-Left Click extend/toggle atom selections.

4. Use <Ctrl>-Left Click to select entire residues.

5. Left-mouse click in empty space to de-select any atoms.

Exercise: Fixing/Unfixing Atoms (Edit | Potential | Fix / Unfix)

Fixing atoms:

1. Left mouse drag to select the atoms to be fixed.

2. Fix the atoms with the command (Edit | Potential | Fix) .

Fixed Atoms do not move until unfixed.

Unfixing atoms:

1. Select the atoms to be unfixed. Use (Selection | Potential | Fix) to select all the fixed atoms.

2. Unfix the atoms with the command (Edit | Potential | Unfix). Once unfixed the atoms may move.

Exercise: Fixed atoms and rotatable bonds

<Alt> Drag

If two atoms in a rotatable bond are selected <Alt>-Left Drag will rotate about the bond. If no atoms are fixed, the small group rotates by default.

The larger group can be forced to rotate by fixing an atom in the smaller group

<Alt> Drag

FIX this atom

Meters and Measurement

• Choose Distances to measure and display the distance between two atoms.

• Choose Angles to measure and display the angle between three atoms.

• Choose Dihedrals to measure and display the dihedral angle between four atoms.

(Edit | Measure) or (RHS | Measure…)

CLI Prompt Menus

One-line CLI Prompt menus occupy the SVL Command Line at the top of the window

Press (Esc) to exit the prompts or choose to delete the process using the ‘Cancel’ button on the top right.

MOE Selection Menu

Invert current selection

Atom Selection Tool for advanced selecting

Save and Restore selection sets

Pull down menus for selection by property, element, extension or other criteria

Deselect all atoms

Knowledge-based selectors for different parts of protein/ligand bound structures

Extend selection set

Selection state of residues is coordinated with the Sequence Editor

The Atom Selector

Other Selection Options:1. Accessibility2. Chirality3. Connectivity4. Geometry5. General6. Pharmacophore7. Protein (e.g. alpha carbon)

Logic Operations

Select by elements and atom types

Extend Selection Criteria

Save and Load selection sets; create named sets

Selection Restrictions

Select by name

Select by SMILES string substructure

General Selection actions

MOE | Selection | Atom Selector

Moving Atoms with the Middle Mouse Button

Middle click to center on atom

Middle Drag:

XY Translate

XY Rotate

<Shift>Middle Drag:

<Ctrl>Middle Drag:

Zoom in/out

center of rotation

<Alt> Middle Drag:

XY Rotate selected only

<Alt> <Shift>-Middle Drag:

XY Translate selected only

Exercise: Moving Atoms with the Middle Mouse Button

1. View the coordinate system (Render | Draw | Coordinate Axes).

2. Rotate view about the XY axes (Middle Drag).

3. Translate view (<Shift>-Middle Drag).

4. Middle click on the carbonyl O to move the center of rotation.

5. Remove the coordinate axes by de-selecting (Render | Draw | Coordinate Axes)

6. Deselect all atoms (Left-click in space or (Selection | Clear)).

7. Move a selected subset with <Alt>-Middle Drag (rotate)<Shift><Alt>Middle Drag (translate).

MOE Render Menu

Center, Save and Load views

Draw H-bonds, VDW contacts, label options, coordinate axes, etc.

Stereo viewing options: Quad-Buffer, Over-Under, Interlace, Left-Right, Parallel

Protein/DNA backbone rendering

Atomic/Molecule object rendering

Hide and Show various sets

Basic coloring

Atom Labeling menu

Detailed atom and label style menu

Setup of default colors and object dimensions.

Exercise: Small Molecule Rendering

Select and render as ‘Space Filling’

Select group and render as ‘Stick’

1. Deselect all atoms.

2. Use Left drag click to select part of the molecule. Render it as space filling(Render | Space Filling).

3. Select other parts of the molecule using left-drag or other methods, and render them as stick, ball and stick, or line.

• Rendering actions apply to:

All atoms (if none are selected)

Selected atoms only (if there are selected atoms)

Protein Backbone Rendering MOE | Render | Backbone

or

MOE | Popup | Backbone

Turn off backbone

Various Backbone rendering styles

Backbone coloring options

Exercise: Open PDB file prior to rendering complex

1. Close the current system: MOE | File | Close

2. Select the file MOE | File | Open $MOE/sample/mol/1pph.pdb.

3. Press ‘Load PDB File’.

4. A variety of options are available in the PDB File panel. Choose to centre the view and press ‘OK’.

Exercise: Rendering Trypsin with Ligand

5. Select the water molecules (Selection | Solvent) and delete them (RHS | Delete).

6. Select the ligand(s) (Selection | Ligand) and render as space filling (Render | Space Filling).

7. Use Render | Color to select a desired colour for the selected atoms (green).

8. Deselect the atoms

9. Draw a backbone ribbon through the selected atoms (Render | Backbone | Slab Ribbon).

10. Color the backbone by Chain Color(Render | Backbone | Color | Chain Color).

11. Hide the selected protein atoms(Render | Hide | Receptor).

12. Click on empty space to clear selection state.

Contact Statistics

Calculate and display probability of finding hydrophobic or hydrophilic contact at a point P relative to an atom. The contacts are derived from PDB x-ray structure statistics.

v

u

rP

Preference for Hydrophilic Contacts

Preference for Hydrophilic Contacts

Preference for Hydrophobic Contacts

Preference for Hydrophobic Contacts

Contact Statistics (cont.)Contact Statistics can be used to highlight directional packing preferences on interaction surfaces:

Hydrophilic contacts for polar H

Hydrophilic contacts for polar H

Hydrophobic contacts above and below pi system

Hydrophobic contacts above and below pi system Interaction Surface

Contacts statistics on top of interaction surface

Exercise: Contact Statistics in Pocket 1. Open the Contact Statistics

panel: MOE | Compute | Surfaces and Maps

2. Setup the panel as follows

Surface: Contact Preference

3. Press Apply.

5. Save to a MOE file (File | Save) ‘trypsin_csats.moe’ toggling on Graphics: All in panel

Exercise: Receptor Molecular Surfaces1. Close the current system. (File | Close).2. Disable hydrogen bond selection by de-selecting MOE | Render | Draw | H bonds3. Open the files

(MOE | File | Open )$MOE/sample/mol/biotin.moe.$MOE/sample/mol/biotin_rec.moe.

4. Calculate partial charge (MOE | Compute | Partial Charge) and enable “Adjust Hydrogens and Lone Pairs as Required”

5. Draw a electrostatic surface about the pocket (MOE|Compute|Surfaces and Maps)

6. Name the surface ‘Pocket Surface’

7. Color by Electrostatics

8. Press Apply

Exercise: Ligand Molecular Surfaces

1. Now draw a molecular surface of the ligand (MOE | Compute | Surfaces and Maps) selecting the defaults, but changing the Name to: Ligand Surface, and selecting Atoms: Ligand Atoms

2. Press Apply

Exercise: Biotin receptor surface (cont.)

To view the different surfaces, go to (MOE | Window | Graphic Object)

Select Pocket Surface

Press Hide

Select both surfaces (Shift Left mouse click)

Press Toggle to switch between surfaces

Surfaces: Backface Culling and Visualization

Note the transparency options for the front (TF), and the back (TB)

Set the slide on TB, and rotate the system to view the backface culling

Ligand Interactions• Automatic 2D protein-ligand interaction diagrams

– Application of MOE's automatic 2D depiction algorithm

– Easily identify polar, hydrophobic, acidic and basic residues

– Visualize solvent exposed ligand atoms and residues

– Visualize sidechain and backbone acceptor and donor interactions

• Visualize 3D Contacts– Display hydrogen bonds between ligand,

receptor/solvent and metal ligation– Score estimates strength of hydrogen bond

• Report protein-ligand interaction data– Textual listing of interactions with scores

• Export 2D schematic to a picture– Choose between png, gif, jpeg, bmp and copy to clipboard

Exercise: 2D Protein-Ligand Interactions

1. Hide all surfaces (MOE | Window | Graphic Object). Select and Hide each surface

2. Open MOE | Compute | Ligand Interactions

Exercise: Protein-Ligand Interactions

substitutioncontour

amount of ligand contact

solventexposure

greasyresidue

acidicresidue

polarresidue

backbone donor/acceptor

sidechain donor

Exercise: Protein-Ligand Interactions

In the main MOE window, observe the relative strength of the ideal hydrogen geometry, shown as dotted lines

1. In the Ligand Interactions panel, select 3D Contact Style

2. Turn ON Residue H-bond Distance. Residue hydrogen bonds are scored and distance metrics are drawn in the main MOE window

2. The Sequence Editor

MOE Window - 3D molecular data is displayed in the Sequence Editor as2D data: bound ligand(s) protein chain(s) water chain(s)

The SE Displays a ‘2D’ view of the molecular data

Objects in SE can be used to manipulate objects in MOE Window (ensure Selection | Synchronize is enabled)

Secondary Structure in SE is displayed as colored bars

Open SE…

(MOE | SEQ) or <Ctrl>-Q

Anatomy of the Sequence Editor (SE)

Chain Label

Chain Number

Residues

Alignment Ruler

Secondary Structure BarsRed = helicesYellow = sheetsBlue/Green = H-bonded Turns

Footer

SE Menu

SE Menu Command Conventions

• Commands from the Sequence Editor are preceded by SE.

(SE | Selection | Residue Selector)

Synchronize selection of objects in MOE Window or DBV (via MOE or SE | Selection | Synchronize)

Data Hierarchy in MOE

Selecting Objects in the Sequence Editor

Left Drag:

Selection Box

Chain Selection: Click: Chains one at a time<Ctrl> Multiple Chains<Shift> a range of chains

Select residues one at a time

Select Multiple Residues

Select range of residues

<Shift>

<Ctrl>

Sequence Editor Popup MenusOpen the SE Popup menus by right-clicking over the areas shown below:

Exercise: Using SE for Protein Rendering

1. Select protein chain (chain 2). Position mouse over chain and use Right mouse button to get Chain popup.

2. Select Backbone | Slab Ribbon, and

3. Backbone |Color | Chain color

4. Hide receptor (Atoms | Hide)

5. Select Chain 1 (ligand) and use popup menu to Render | Space Filling

Exercise: Using SE for Protein Rendering (cont.)

6. Close the current system (MOE | RHS | Close)

7. Close all windows except the main MOE window

3. The MOE Database Viewer

Character, numeric and molecular data fields

Molecular Data easily transferred between database and MOE Window

Full 3D molecular structure

Anatomy of the Database Viewer (DBV)

DBV CLI

Entry Numbers

Field Headers

Data Cells

Menu Bar

DBV Menu Command Conventions

• Commands from the Database Viewer preceded by DBV

(DBV | Entry | Show All Entries)

DBV Left Mouse Button Commands

Select entries/fields one at a time

Select multiple entries/fields

Select range of entries/fields

<Shift>

<Ctrl>

DBV Popup MenusThe Popup Menus are invoked with the right mouse button

Exercise: Opening a MOE Database Viewer

1. (File | Open) Select the file $MOE/sample/mol/opiates_analog.mdb.

2. Open in a database viewer (Open in Database Viewer).

Exercise: Opening a MOE Database Viewer (cont.)

XY Rotate

<Ctrl>Middle Drag:

Zoom in/out

3. Left-Diagonal drag on a molecule cell to enlarge it.

4. Middle-drag in the molecule cell to rotate the view.

Enlarge Molecule View: Left Diagonal Drag on Molecule Cell

Middle Drag:

Exercise: Database Printing and Tiling1. (DBV | File | Print)

2. Click on ‘Tile Molecule Field’.

3. Select ‘Display Entry Number’ and choose the footer to be the field ‘name’.

4. Change Grid: 3x4

Exercise: Copying Morphine from the DBV

2. Copy morphine (entry 1) to the main MOE window by Left-double-mouse click in the mol field

3. Select ‘Clear Molecular Data’

4. Render as stick (MOE | Render | Stick)

1. Close the current system in the MOE Window.

Exercise: Protonate the nitrogen atom in morphine

1. Left-click on the nitrogen atom, so that it becomes highlighted.

2. Left-click on the ‘Builder’ button on the RHS of the menu bar.

3. Select +1 for the ionisation state.

4. The nitrogen atom is then protonated.

• Aims to predict the structure and properties of molecules. • Uses a Force Field with parameters from known structures• Energy Minimization calculates the energy of a molecule

and adjusts the structure to obtain a lower energy structure.• Predicting short-range steric interactions is easy and

accurate• Predicting long-range electrostatic interactions and the

effect of water is difficult.• Flexible molecules may need to be described with an

ensemble of conformations.

Molecular Mechanics

Potential Energy in MOE

Toggle on/offterms in the potential

Partial charge calculation according to selected potential

E = ESTR + EANG + ESTB+ ETOR + EOOP + EELE + EVDW + ESOL

Load different forcefields

Forcefield parameter file

Forcefield title

No. of parallel processor threads to be used

Adjustelectrostatics implementation

Adjustnon-bonded interaction switchingfunction

Supported Forcefields

Biopolymers (proteins and nucleic acids)

AMBER 89, AMBER 94, AMBER 99, CHARMM 22, CHARMM 27, OPLS-AA

Small Molecules

MMFF94, MMFF94s, MMFF94x

Crystallographic

Engh-Huber

Carbohydrate

PEF95SAC

Simple Molecular Modelling

Rule

Exercise: Forcefield Energy Minimizations (1)

Click on arrow by Load

Select the MMFF94 potential

Select ‘Fix Charges’ to assign atomic charges according to the chosen potential

1. First choose an appropriate potential and partial charges in MOE | Window | Potential Setup

2. Press OK and Close

System energy components

2. Choose MOE | Compute | Potential Energy


Potential energy components are also shown in the SVL window

Tether Weight

(kcal/mol A2)

Automatically assign partial charges

Automatically add H’s (and LPs if required)

Force current (R/S) stereochemistry

• Minimizations may be forcefield, or semi-empirical (MOPAC 7) Hamiltonian based

Potential Setup window


Minimized Morphine


3. Use the defaults in the panel and press OK

To minimize the molecule, select (MOE | Compute | Energy Minimize)

PM3, AM1 or MNDOOption to plot and view orbitals (HOMO and LUMO)

Exercise: MOPAC Minimization

Select (MOE | Compute | Energy Minimize)

To view HOMO/LUMO orbitals go to (MOE | Window | Graphic Objects)

1. Close the current system (RHS | Close)2. Open biotin and its receptor (MOE | File | Open

‘$MOE/sample/mol/biotin.moe and biotin_rec.moe’3. Add Hydrogen atoms and compute partial charges (MOE

| Compute | Partial charge)4. Select the ligand. Right click in the main MOE window to

get popup panel. Popup | Select | Ligand5. Choose MOE | Compute | Potential Energy

Calculating Interaction Potential Energies

ALL: total system E

INT: selected – unselected interaction E

SEL: selected only E

Exercise: Dihedral Energy Plots

1. Close current system. Open $MOE/sample/mol/biotin.moe

2. Add hydrogen atoms (MOE | Edit | Hydrogens | Add Hydrogens)

3. Open the dihedral energy plot panel: MOE | Compute | Mechanics | Dihedral Energy Plot.

4. Select four consecutive carbon atoms in a dihedral.

• Plots the energy about a single rotatable bond.

Exercise: Dihedral Contours

1. Open the Dihedral Contour prompt (MOE | Compute | Mechanics | Dihedral Contour Plot).

2. Select four consecutive carbon atoms in one dihedral, followed by four consecutive carbon atoms in another dihedral.

• Plots the energy contours about two rotatable bond.

Forcefield Restraints: Energy terms

ERESTRAINT = EDistance + EAngle + ETorsion

• The restraint energy is a sum of all the individual restraints:

• When restraints are set, their energy and forces are included in ALL MM based calculations.

EDistance

EAngle

ETorsion

Creating Forcefield Restraints

EDistance

EAngle

ETorsion

= ( max (0, L2 - r2)3 + max (0, r2 - U2)3 ) * w

= (max(0, cos a - cos L)3 + max(0, cos U - cos a)3 ) * 100 w

= ( (1 - cos max(0,d - L))3 + (1 - cos max(0,U - d))3 * 10000w

• Restraints are created from the MOE | Edit | Potential | Restrain command.

• The type of restraint and the parameters are set in the following CLI prompters.

• ‘Create’ must be pressed to create the restraint.

Exercise: Creating Forcefield Restraints

1. To create a distance restraint open (MOE | Edit | Potential | Restraint). Select the acid oxygen and a hydrogen alpha to it. Set the Target Limits as (L = 3.0, U = 3.5, w = 1). Press Create.

2. Similarly, create an angle restraint (L = 1150, U = 1350 , w = 1) between the carboxylate C and the O and H atoms shown here.

3. Minimize the structure (Compute | Energy Minimize).

Minimized with restraints

The Tethers and Restraints PanelThe Tethers and Restraints panel (Window | Potential Setup | Restraints) can be used to manage and edit current restraints.

Toggle ‘Restraints’ to display restraints

List of current restraints

Edit selected restraint.

Press ‘Apply’ to institute changes.

Delete selected restraints

Exercise: Removing Restraints

1. Open the Tethers and Restraints panel (Window | Potential Setup | Restraints).

2. Delete all the current distance and angle restraints.

3. Re-minimize the molecule (Compute | Energy Minimize).

Minimized without restraints

Minimized with restraints

Exercise: Using the GizMOE Minimizer

1. With biotin in the system, start the GizMOE Minimizer.

MOE | GizMOE | Minimizer

2. Left drag to select and move part of the molecule. Then watch how the energy and geometry are automatically updated.

The GizMOE Minimizer is a minimizer that runs continuously in the background.

3. Turn off the GizMOE Minimizer. Click the Cancel button and choose GizMOE_Minimizer[]. If necessary re-minimize the system (RHS | Minimize)

<Alt><Shift>Drag

Translate Selected Atoms Only

Conformational Searching

Systematic Conformational Search

Stochastic Conformational Search

Conformational Database Import

Molecular Dynamics

• Conformational search methods available in MOE

• Generation of different conformations of a molecule or a complex is very useful for drug design.

Stochastic Conformational Search

Torsion Space

E

EnergyCutoff

E0

1. Perturb geometry

2. Minimize

• Random sampling of local minima on the potential energy surface

Stochastic Conformational Search Panel

Output database

Randomly:Invert chiral centers

Rotate torsions

Perturb xyz coordinates

Conformation Generation:

Conformation Minimization:

Systematic Conformational Search

• Exhaustive incremental dihedral rotation search

Torsion Space

E

Cutoff

E0

Systematic Conformational Search Panel

Set dihedral increment

Add/Remove dihedrals from list

Output Database

Minimise structures

List of bonds to undergo rotation

Exercise: Systematic Conformational Searching (1)

1. Close the current system (RHS | Close)

2. Open up the MOE file for the molecule built earlier (MOE | File | Open ‘my_first_molecule.moe’).

3. Perform a systematic search on this molecule using the default options(MOE | Compute | Conformations | Systematic Search)

4. Left-Drag in DBV molecule cell to view structures.

Enlarge Molecule View: Left Diagonal Drag on Molecule Cell

1. Open (DBV | Compute | Descriptors).

2. Enter ‘Energy’in the Filter field.

3. Select the descriptor (Left mouse click once) “E Potential Energy” and press OK.

Exercise: Systematic Conformational Searching (2)

Exercise: Sorting and Selecting Conformers2. Left double click on the

lowest energy conformer in the mol field to copy to the MOE Window.

1. Position the mouse over the E Field. Right click to use Field Header popup to Sort UP on energy.

Superposing Conformations

Mol field to perform calculations on

Database to perform calculations on

Measurementsto perform on database

Superposition of conformers in database

Auto-Label atoms by element and number

Exercise: Superposing Conformations

1. Left mouse drag to select the methyl substituted pyridine ring

2. Bring up the Conformation Geometries panel. (DBV | Compute | Conformation Geometry…)

3. Change Molecule Field: to Overwrite Current Field.

4. Click on the Selected Atoms buttons.

5. Click on the Superpose button.

Exercise: Superposing Conformations (cont.)

6. Shift Left mouse click over a subset of entries (try entries 1 to 5)

7. Use Molecule Cell popup to Copy Selected Entries to MOE Window

8. Observed the superposed conformations

9. Color by chain using (MOE | Popup | Color | Chain)

Diverse Conformational Subset

1. Open the Diverse Subset panel (DBV | Compute | Diverse Subset).

2. Set the Output Limit to 20.

3. Choose ‘Conformation’ as the selection method.

4. Press OK to start calculation.

Exercise: Diverse Conformers Subsets

6. Copy 20 diverse conformers to MOE with popup. Shift Left click over entries 1 to 20.

7. Position mouse in mol field and use Right mouse button to get Popup. Select Copy Selected to MOE

8. Remember to select Clear Molecular Data

9. Render conformers as stick (MOE | Render | Stick)

5. Use Field popup to Sort Up on $DIVPRIO.

Interactive Superposition

• Edit | Interactive Superpose is a tool for optimally superposing molecules based on selected point sets.

• More than two structures may be superposed simultaneously.

Exercise: Interactive Superpose (1)1. Close the current system and open (File |

Open) $MOE/sample/mol/opiate_analogs.mdb

2. Select entry 1 and 7 (morphine and heroin). Copy to MOE window

3. If molecules are superposed, separate by Ctl-Left click on an atom of one molecule, to select entire molecule.

4. Separate by moving selected molecule using Shift-Alt-Middle mouse

5. Center the view (RHS | View).

6. Render the structures as ball and stick (Render | Ball and Stick).

7. Hide the hydrogens (Render | Hide | Hydrogens).

8. Initiate superpose (Edit | Superpose).

1

1

2

2 3

3

Exercise: Interactive Superpose (2)

6. For Set 1 select the indicated oxygens labelled (1) on each molecule

7. Press Set: 2 in the CLI prompt and select the indicated aromatic ring carbons labelled (2)

8. Press Set: 3 in the CLI prompt and select the indicated oxygen atoms directly connected to the benzenes labelled (3)

9. With the minimum 3 point sets specified, the Superpose is possible. Press Superpose to superpose the structures.

10. Pressing Superpose will superpose the structures based on an optimal RMSD.

Flexible Alignment of Small Molecules

- Feature-based alignment of 2 or more molecules

- Features are pharmacophore-like

- Stochastic search algorithm employed for flexibility

- Weighting scheme for features

Exercise: Flexible Alignment of Opiates (1)

1. Close the current system (RHS | Close) and import morphine, heroin and demerol (entries 1, 7, 11) from the database $MOE/sample/mol/opiate_analogs.mdb

2. Ensure that the partial charges have been set, using MOE | Compute | Partial Charges.

3. Select one of the molecules using Ctl-Left mouse click on an atom of one molecule and fix it: MOE | Edit | Potential | Fix.

6. Choose MOE | Compute | Conformations| Flexible Alignment. Decrease the iteration limit down to 20, instead of 200.

Similarity terms and weighting

7. Preserve defaults and press OK


8. Let the application run to completion.

9. Sorting in S occurs automatically

10. Choose the “best” alignment

“Best” may be that with the lowest scoring function value – but take strain into account!


11. Copy the “best” alignment into the MOE Window.

- Aligning multiple molecules can be time-consuming; try aligning them one at a time, keeping the earlier alignments fixed.


Exercise: Rendering of the Flexible Alignment

Select MOE | Render | Color | Chain. This will colour the chains (i.e. separate molecules) of the flexible alignment.

Close the current system (RHS | Close)

Close all windows except the main MOE window

Further Simulation Techniques

• Poisson-Boltzmann electrostatics

e.g. analysis of active site in a receptor can reveal the effect of the surrounding residues on the binding properties of a ligand.

Solution of the full non-linear PB equation, allowing for different ion classes, radii and partial charges.

• Molecular Dynamics

e.g. use to relax structures and to generate conformational states at a desired temperature and/or pressure (in NPT, NVT, NVE, NPH).

Further Simulation Techniques

• Docking

• Flexible ligands and a rigid receptor. The poses may be constrained to fit a pharmacophore query.

• Affinity dG scoring is used to estimate the enthalpic contribution to the binding free energy of hydrogen bonding, ionic, metal ligation and hydrophobic interactions.

Introduction to Database Viewer Analysis

Used for:

•Cheminformatics•QSAR•Clustering•Similarity Search•Diverse Subsets•Fingerprints•Library Generation/Design•Ph4 applications

•Output for•Conformation search•Dynamics •Flexible alignment•Docking

•Washing / Processing

Exercise: Opening a MOE Database Viewer

1. (File | Open) Select the file $MOE/sample/mol/blood_brain.mdb.

2. Open in a database viewer (Open in Database Viewer).

3. Save a local copy (DBV | File | Save ‘bbb.mdb’)

Exercise: Calculating Descriptors

1. Open the QuaSAR-Descriptor panel (DBV | Compute | Descriptors).

Descriptor Filter

2. On the Filter line, type TPSA. Left click once on TPSA in the panel to select.

3. Repeat to select Weight, logP(o/w), and MR

4. Press OK and descriptors will be calculated into the database

Exercise: Sort by Activity

1. Open the Sort Database panel (DBV | Compute | Sort).

2. Select Field: “logBB”

3. Enable “Descending”4. Press OK

• Sort in descending order of logBB

Exercise: Plotting Data

1. Open the DBV Plot window (DBV | Display | Plot).

2. Select logBB as the numeric value to plot.

3. Use the Right button in the plot area to compute the range with the DBV Plot popup.

Mouse Actions in the DBV Plot Window

Drag: Selection Box

Left Click:Select points individually

Drag on axis: Selection Range

XY Translate

Plot

<Shift> Drag:

<Ctrl>Drag: Zoom

in/out of Plot

Entry Selection is reflected in the DBV and the DBV Plot window

Exercise: Select actives

2. Notice selected entries are updated automatically in the database viewer

1. Select active compounds by using Left mouse drag in Plot:Display for all entries where logBB > 0.

• Select compounds with logBB > 0

Exercise: Hide Inactives

1. Since all compounds with logBB > 0 are selected, go to (DBV | Entry | Hide Unselected entries)

2. Use the Right button in the plot area to compute the range

• Hide all compounds with logBB < 0

Exercise: Look at active compounds

1. Launch database browser by going to (DBV | File | Browser)

3. Use forward/backward triangles to navigate

2. Select Subject:mol (2D) for depicted mode

Exercise: Show relationship between all fields1. Start the database correlation matrix prompt (DBV | Compute | Analysis |

Correlation Matrix…).

2. Press on TPSA/logBB to get same correlation plot

Exercise: Select actives

Entry Selection is reflected in both the DBV and Correlation Plot

Drag: Selection Box

Use the Attributes menu to change look of the plot

Select points in the plot:

Exercise: Show relationship of actives with logP(o/w)

1. Hide inactives, go to (DBV | Entry | Hide Unselected entries)

2. Start the database correlation plot prompt (DBV | Compute | Analysis | Correlation Matrix…).

3. Press on logP(o/w) / logBB to get correlation plot

Pharmacophore Overview

Aim: to find chemically unrelated molecules which share molecular features

3. Take conformations of a set of diverse molecules.

4. Annotate with PH4 features

5. Find hits whichmatch the query.

1. Take an active molecule.

2. Annotate possible PH4 features

3. Create a query with these features

HB Acceptor

HB Acceptor

Aromatic

Compute | Conformations | Pharmacophore Elucidation

ObjectiveStarting from single conformations of active and inactive compounds, sample conformations on the fly and automatically extract maximum common Ph4 pattern which selectively recognizes active features.

Activity threshold: binary or no activity

Activity threshold: binary or no activity

Selection of Ph4 schemes that can be stored and loaded

Selection of Ph4 schemes that can be stored and loaded

Specification of conformational method

Specification of conformational method

Modification of features / rules

Modification of features / rules

Output databaseOutput database

Ligand databaseLigand database

Pharmacophore search parameters

Pharmacophore search parameters

Feature list and feature properties

Feature list and feature properties

Parameters for structure alignment

Parameters for structure alignment

Text reportText report

Exercise: Pharmacophore Elucidation I

1. Open Elucidator panel in (MOE | Compute | Conformations | Pharmacophore Elucidator)

2. Choose an output database name(default: ph4elucidate.mdb)

3. Browse to select as Input Database: $MOE/sample/mol/1RO6_ligands.mdbThis has 7 ligands from pdb structures

4. Switch the Conformations setting to Bond Rotation. Leave the Activity Field as “All Active” since all ligands are active in this example (otherwise you would select the activity/inactivity threshold here)

5. Remain with the default Ph4 scheme (CHD) and click OK.

The Elucidator will try to identify popular Ph4 patterns from sets of unaligned molecules. To validate the performance of the Elucidator, we will start with an example where we know the “optimal” result (aligned by nature in X-ray protein structures):

Pharmacophore Elucidation II

The output database looks like…

Conformations of Ph4 alignment

Conformations of Ph4 alignment

Query features:D/A = heavy atom Don/Accd/a = projected Don/AccH = Hyd/Arom = Metal+/- = Cation/Anion

Query features:D/A = heavy atom Don/Accd/a = projected Don/AccH = Hyd/Arom = Metal+/- = Cation/Anion

Active molecules

Active molecules

Separation of actives/inactives

Separation of actives/inactives

Accuracy of actives

Accuracy of actives

Alignment score

Alignment score

Probability by chance

Probability by chance

Query information for DB Browser

Query information for DB Browser

Accuracy of inactives

Accuracy of inactives

Total Number of features

Total Number of features

Number of features of specific type

Number of features of specific type

Exercise: Pharmacophore Elucidation III

The output database is sorted by ascending overlap (alignment) score.

6. Use (DBV | File | Browser) to examine each Ph4 alignment.

Note the modified view of the browser

while displaying the results.

You may want to modify input parameters in your elucidator calculation interface if you are not satisfied with the quality of the results or you may directly edit the underlying queries to further refine the results.

You may want to save the current Ph4 query or modify the features of a given entry. Double-clicking in the query cell in the Database Viewer will launch the Ph4 Query Editor. Edit in the Database Browser brings up the Ph4 Query Editor.

4. The SVL Commands Window

1. Open the SVL Commands Window with (RHS | SVL)

SVL is a powerful language designed to allow you to customize MOE and extend MOE with your own functions

Exercise: SVL Commands Window

1. SVL commands are prefixed in the text with svl>. For example, enter 3+4 in the SVL Commands Window:

svl> 3+4 Press Enter 7

2. SVL commands can be used to open menus and build molecules from SMILES strings For example, build methane by entering

svl> sm_Build ‘C’

Basic SVL windows in MOEText Editor (TED)

ASCII file / SVL program editor

Crash History

Source-level error trace-back

Modules & Tasks Manager

Program control / Source Code

Appendices

Forcefield File alkane.ff: Atom Typing Block

#moe:forcefield 2000.02

#comment lines

title ALKANE

disable oop stb itortype

CT C 'sp3 C'type

HC H 'H attached to alphatic

C'[rules]

#--------TYPE ASSIGNMENT RULES --------

CT match '[CX4]‘

HC match '[#1]C‘

…

Forcefield File alkane.ff: Bond Stretch Block

[str] #--------------------- BOND STRETCH ---------------------

#code T1 T2 LEN K2 K3 K4 bci

#----- ---- ---- ---- ---- ---- ----- ----

* CT CT 1.518 448.2 -1010.6 1329.08 -

* CT HC 1.090 334.2 -606.37 641.608 -

ij

ijijijijijijijijijSTRSTR LrKLrKLrKwE 432 )(4)(3)(2

Forcefield File alkane.ff: Angle Bend Block

[ang] #------------------ ANGLE BEND ---------------------

ang-function angle

#CODE T1 T2 T3 ANG K2 K3 K4

#--- ---- ---- ---- ----- ----- --- -----

* CT CT CT 109.50 86.97 0.00 0.00

* CT CT HC 109.50 87.15 0.00 0.00

* HC CT HC 109.50 74.07 0.00 0.00

ijk

OijOijOijANGANG KKKwE 432 )(4)(3)(2

Forcefield File alkane.ff: Torsion Block

[ptor] # ------------- proper torsion ----------------------

# T1 T2 T3 T4 V1/2 V2/2 V3/2 V4/2 V5/2

# -- -- -- -- ---- ---- ----- ---- ----

* CT CT CT CT 0.00 0.00 1.606 0.00 0.00 1

* CT CT CT HC 0.00 0.00 0.250 0.00 0.00 1

* HC CT CT HC 0.00 0.00 0.221 0.00 0.00 1

ijkl

ijklijklNN

TORTOR NKwE )cos(1;

5

1

Forcefield File alkane.ff: Electrostatics Block

[nonbonded] # ------ nonbonded information ----------

ele-dielectric 1 # dielectric+distance dependent flag

ele-buffer 0 # electrostatic buffering

ele-scale14 1 # 1-4 interaction scaling

ele-charge-fcn alkane # svl fcn to compute charges

ji N

kELEij

jiELEELE br

qq

d

ewE

5

10

2

)(4

Forcefield File alkane.ff: VDW Block

vdw-scale14 1

[vdw] # ------- VDW PARAMTERS ----

#T1 T2 R EPS m n

#--- ---- ------- ------- -- --

CT CT 3.6458 0.21949 12 6

CT HC 3.5834 0.01799 12 6

HC HC 3.5220 0.001475 12 6

ji ij

ijij

mij

mij

mij

ij

ij

n

ijij

ijijVDWVDW m

nm

bRr

Rb

m

n

aRr

RawE

ijij

ijij

)(

)1()1(

Visualization Setup: Coloring

Set colors of objects

Press Apply to institute changes

Restore defaults

Save new settings as defaults

MOE | Render | Setup…

Visualization Setup: Dimensions

Protein Ribbon dimensions

Atom and Bond dimensions

Visualization Setup: Lighting and Projection

SVL and MOE-batch

• MOE/batch

• Terminal-style interface (no GUI).

• SVL commands entered at prompt.

• Used for scripting long tasks and automating procedures.

the main moe windows

Documents

moe moe

moeopen moe file

moe windowused

file cont

moe database viewerused

file open panel file

text editoropen file

variety of export file