The Main MOE Windows
The MOE Window
(MOE) or ( )
Small molecule
bioinformatics,
Molecular
mechanics, Small
molecule
visualization,
Forcefield
applications
MOE Database
Viewer (DBV)
Cheminformatics,
conformational
search, fingerprints,
clustering,
combinatorial library
design
SVL Commands Window (CLI)
Custom SVL, interactive scripting,
session logging
Sequence Editor (SE)
Protein bioinformatics, homology
modeling, sequence analysis
Intro 1: The MOE Window
Used 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 Editor
Used 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
4.
a)
Basics of molecular mechanics and conformational
searching
b)
Basics of cheminformatic analysis with the Database
Viewer
Comments on SVL
1. Structure of the MOE Window
Task Cancel
Button
Main Menu
Commands
RHS Button
Bar
SVL Command
Line
Popup menu
3D Rendering
Area
Footer Pager Bar
MOE Menu Command Conventions
• Commands from the MOE Window are preceded by MOE or ()
(Render | Backbone | Color | Chain Color)
or
(MOE | Render | Backbone | Color | Chain Color)
Mouse Conventions in MOE
General Mouse Actions
LEFT
3-Button Mouse –
2-Button Mouse Mapping
- Selecting objects,
menu commands
MIDDLE
- Rotating,
translating moving
objects
RIGHT
- SE and DBV Popup
menus
Press and release <Alt>
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)
Path Text
Field
Current Path/
Directory
Change Working
Directory (CWD)
Enforce
File Type
‘..’
go up a
Directory
Recent
Directories
List
Directory/
File List
Open file
into MOE
Open file in
text editor
Operations to
Perform on
selected file(s)
Exercise: Opening a File
1. Open the File Open panel (File | Open).
2. Use the pull-down menu to switch to the $MOE/sample/mol
directory.
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.
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 click:
Change center of
rotation
Right
Click:
Popup
menu
Left Click in
Empty Space:
To de-select to
clear
Middle
Drag:
Left Drag:
Selection Box
XY
Rotate
Ctrl Middle Drag
or Scroll wheel
Zoom in/out
Exercise: Render molecule
• Render as ball and stick, label all atoms by name, and show H-Bonds
1.
MOE | Render | Draw | Hydrogen Bonds
2.
Mode | Ball and Stick
3. Label | Name
4. Label | Clear
Exercise: Saving a picture (1)
1. Choose MOE | File | Save
2. Click on MkDir to create a new
directory called ‘course’
3. Click on Set CWD to set as
the new working directory
Exercise: Saving a picture (2)
4.
5.
6.
7.
Choose Save ‘Picture’
Enter the filename ‘sulph_quin.png’
Choose Format ‘PNG’
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
Drawing Molecular Surfaces
• 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)
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
Exercise: Outputting the system… to the printer
To print the current MOE 3D window choose MOE | File | Print...
Printer or Postscript file
Landscape/Portrait
Header
Footer
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
Other atom types,
including dummy
atom at centroid
Edit or Add Element
Edit Ionization
State
Fragment substitution
buttons
Edit Chirality
Enter Fragment SMILES
string
Edit:
1. Compound Name
2. Bond Length
3. Bond Angle
4. Torsion
Undo button
Library of
functional groups
Exercise: Build a molecule
Press
Select C
Select C
Press
Press
Exercise: Build a molecule (cont.)
Press
Shift-select 2 C
<Shift>
Shift-select 2 C
Press
<Shift>
Exercise: Build a molecule (cont.)
Select H
Press
Select H
Press
4 times
Exercise: Build a molecule (cont.)
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
Protein and Carbohydrate Builders
MOE | Edit | Build |
Protein
or
SE | Edit | Protein Builder
MOE | Edit | Build | Carbohydrate
Selecting Atoms with the Left Mouse Button
<Ctrl>-Left Click:
Auto-extend selection to residue
Left Click:
Select atoms
one at a time
<Ctrl>
<Shift>
<Shift>-Left
Click:
Add to / toggle atom
selection
Left Drag:
Selection Box
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
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.
<Alt>
Drag
The larger group can be forced to rotate by fixing an atom in the smaller group
FIX this
atom
<Alt>
Drag
Meters and Measurement
(Edit | Measure)
or (RHS | Measure…)
• 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.
Meters – Creating and Removing
To create a meter, choose MOE | Edit | Measure | Distances. To remove it,
select the atoms involved, and use RHS | Remove | Distances.
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
Extend selection set
Deselect all atoms
Invert current selection
Knowledge-based
selectors for different
parts of protein/ligand
bound structures
Atom Selection Tool for
advanced selecting
Save and Restore
selection sets
Selection state of residues is
coordinated with the Sequence Editor
Pull down menus
for selection by
property, element,
extension or other
criteria
The Atom Selector
MOE | Selection | Atom Selector
Selection Restrictions
General
Selection
actions
Logic Operations
Save and Load
selection sets;
create named sets
Select by elements
and atom types
Select by name
Select by
SMILES string
substructure
Other Selection Options:
1. Accessibility
2. Chirality
3. Connectivity
4. Geometry
5. General
6. Pharmacophore
7. Protein (e.g. alpha carbon)
Extend
Selection
Criteria
Moving Atoms with the Middle Mouse Button
XY Rotate
Middle
Drag:
XY Translate
<Shift>
Middle
Drag:
Zoom in/out
<Ctrl>
Middle
Drag:
center of
rotation
Middle click
to center on
atom
<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, OverUnder, 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
• Rendering actions apply to:
All atoms (if none are selected)
Selected atoms only (if there are selected atoms)
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.
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.
Exercise: Protein-Ligand Pocket Rendering
1. Turn the backbone off
(MOE|Popup|Backbone|None)
2. Show ligand and pocket
(MOE|Popup|Show|Ligand,
Pocket)
3. Label the residues (MOE | RHS |
Label | Residue)
4. Draw H-bonds (Render | Draw |
Hydrogen Bonds)
5. Center the image (RHS | View)
which should now look like the
image on the left.
6. Save the system as a MOE file,
MOE | File | Save
trypsin_pocket.moe
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.
Preference for
Hydrophilic Contacts
r
P
v
u
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
Hydrophobic contacts above
and below pi system
Contacts statistics on top of
interaction surface
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 Surfaces
1. Close the current system. (File | Close).
2. Disable hydrogen bond selection by de-selecting MOE | Render | Draw |
H bonds
3. 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: Receptor Molecular Surfaces
1. To isolate the pocket atoms,
press Isolate on the panel
2. Turn off backbone
(MOE|Popup|Backbone|None)
3. Select the pocket atoms
(MOE|Popup|Select|Pocket)
4. Label the residues with the
residue name
(MOE|RHS|Label|Residue)
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
acidic
residue
amount of
ligand contact
polar
residue
substitution
contour
solvent
exposure
sidechain donor
backbone
donor/acceptor
greasy
residue
Exercise: Protein-Ligand Interactions
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
In the main MOE window, observe the
relative strength of the ideal hydrogen
geometry, shown as dotted lines
2. The Sequence Editor
The SE Displays a ‘2D’ view of the molecular data
Open SE…
(MOE | SEQ) or
<Ctrl>-Q
MOE Window - 3D
molecular data is
displayed in the
Sequence Editor as
2D data:
bound ligand(s)
protein chain(s)
water chain(s)
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
Anatomy of the Sequence Editor (SE)
SE
Menu
Alignment
Ruler
Chain
Label
Residues
Chain
Number
Footer
Secondary Structure Bars
Red = helices
Yellow = sheets
Blue/Green = H-bonded Turns
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
Exercise: Molecular Hierarchy
1. For the loaded biotin-streptavidin system, toggle off the molecular surfaces,
at MOE | Windows | Graphic Objects. Select the surface and press Hide.
2. Show receptor, using MOE | Render | Show | Receptor.
3. Clear Labels (MOE | RHS | Label | Clear)
4. Open the Sequence Editor (MOE | SEQ). The system should appear as
shown:
4. Click in empty space to clear
selection state
Exercise: Molecular Hierarchy (cont.)
5. Color the atoms by chain color (MOE | Render | Color | Chain)
6. Turn on the compound names (SE | Display | Compound Name)
7. Turn on the secondary structure color bars
(SE | Display | Actual Secondary Structure).
Selecting Objects in the Sequence Editor
Select residues
one at a time
Select Multiple
Residues
Select range of residues
<Shift>
<Ctrl>
Chain Selection:
Click: Chains one at a time
<Ctrl> Multiple Chains
<Shift> a range of chains
Left Drag:
Selection
Box
Sequence Editor Popup Menus
Open 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
Molecular Data easily transferred
between database and MOE Window
Character,
numeric
and
molecular
data fields
Full 3D
molecular
structure
Anatomy of the Database Viewer (DBV)
Menu Bar
Field Headers
DBV CLI
Entry Numbers
Data Cells
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
<Ctrl>
<Shift>
DBV Popup Menus
The 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.)
3.
Left-Diagonal drag on a molecule cell to enlarge it.
4.
Middle-drag in the molecule cell to rotate the view.
XY Rotate
Enlarge Molecule
View: Left
Diagonal Drag on
Molecule Cell
Middle
Drag:
Zoom in/out
<Ctrl>
Middle
Drag:
Exercise: Database Printing and Tiling
1. (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
1. Close the current system
in the MOE Window.
2. Copy morphine (entry 1)
to the main MOE
window by Left-doublemouse click in the mol
field
3. Select ‘Clear Molecular
Data’
4. Render as stick (MOE |
Render | Stick)
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.
Molecular Mechanics
• 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.
Potential Energy in MOE
E = ESTR + EANG + ESTB+ ETOR + EOOP + EELE + EVDW + ESOL
Forcefield title
Toggle on/off
terms in the
potential
Adjust
non-bonded
interaction
switching
function
No. of parallel
processor
threads to be
used
Forcefield
parameter file
Load different
forcefields
Adjust
electrostatics
implementation
Partial charge
calculation
according to
selected
potential
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)
1. First choose an appropriate potential and partial charges in MOE |
Window | Potential Setup
Click on arrow by Load
Select the MMFF94
potential
Select ‘Fix Charges’ to
assign atomic charges
according to the
chosen potential
2. Press OK and Close
Exercise: Forcefield Energy Minimizations (2)
2. Choose MOE | Compute | Potential Energy
System energy
components
Potential energy components are also shown in the SVL window
Exercise: Forcefield Energy Minimizations (3)
• Minimizations may be forcefield, or semi-empirical (MOPAC 7)
Hamiltonian based
Automatically add H’s
(and LPs if required)
Automatically assign
partial charges
Force current (R/S)
stereochemistry
Tether Weight
(kcal/mol A2)
Potential Setup window
Exercise: Forcefield Energy Minimizations (4)
To minimize the molecule, select (MOE | Compute | Energy Minimize)
3. Use the defaults in the panel and press OK
Minimized Morphine
Exercise: MOPAC Minimization
Select (MOE | Compute | Energy Minimize)
PM3, AM1 or MNDO
To view HOMO/LUMO orbitals
go to (MOE | Window |
Graphic Objects)
Option to plot and view
orbitals (HOMO and LUMO)
Calculating Interaction Potential Energies
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 | Ligand
5. Choose MOE | Compute | Potential Energy
ALL: total
system E
SEL:
selected
only E
INT: selected –
unselected
interaction E
Exercise: Dihedral Energy Plots
• Plots the energy about a single rotatable bond.
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.
Exercise: Dihedral Contours
• Plots the energy contours about two rotatable bond.
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.
Forcefield Restraints: Energy terms
• The restraint energy is a sum of all the individual restraints:
ERESTRAINT = S EDistance + S EAngle + S ETorsion
ETorsion
EAngle
EDistance
• When restraints are set, their energy and forces are included in ALL MM
based calculations.
Creating Forcefield Restraints
• 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.
EDistance
= ( max (0, L2 - r2)3 + max (0, r2 - U2)3 ) * w
EAngle = (max(0, cos a - cos L)3 +
max(0, cos U - cos a)3 ) * 100 w
ETorsion= ( (1 - cos max(0,d - L))3 + (1 - cos max(0,U - d))3 * 10000w
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.
Minimized
with restraints
3.
Minimize the structure (Compute | Energy Minimize).
The Tethers and Restraints Panel
The 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
with restraints
Minimized
without restraints
Exercise: Using the GizMOE Minimizer
The GizMOE Minimizer is a minimizer that runs continuously in the
background.
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.
<Alt>
<Shift>
Drag
Translate
Selected
Atoms Only
3.
Turn off the GizMOE Minimizer. Click the Cancel button and choose
GizMOE_Minimizer[]. If necessary re-minimize the system (RHS |
Minimize)
Conformational Searching
• Generation of different conformations of a
molecule or a complex is very useful for drug
design.
• Conformational search methods available in MOE
Systematic Conformational Search
Stochastic Conformational Search
Conformational Database Import
Molecular Dynamics
Stochastic Conformational Search
• Random sampling of local minima on the potential energy
surface
E
1. Perturb
geometry
Energy
Cutoff
2. Minimize
E0
Torsion Space
Stochastic Conformational Search Panel
Conformation
Generation:
Output database
Randomly:
Invert chiral centers
Rotate torsions
Perturb xyz
coordinates
Conformation
Minimization:
Systematic Conformational Search
• Exhaustive incremental dihedral rotation search
E
Cutoff
E0
Torsion Space
Systematic Conformational Search Panel
Add/Remove
dihedrals
from list
Set dihedral
increment
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
Exercise: Systematic Conformational Searching (2)
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: Sorting and Selecting Conformers
1. Position the mouse over the E
Field. Right click to use Field
Header popup to Sort UP on
energy.
2. Left double click on the
lowest energy conformer in
the mol field to copy to the
MOE Window.
Superposing Conformations
Database to perform
calculations on
Mol field to perform
calculations on
Measurements
to 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
5. Use Field popup to Sort Up on $DIVPRIO.
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)
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.md
b
1
2
3
2
1
2. Select entry 1 and 7 (morphine and heroin).
Copy to MOE window
3
3. If molecules are superposed, separate by CtlLeft 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).
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.
2.
3.
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
Ensure that the partial charges have been set, using MOE | Compute | Partial
Charges.
Select one of the molecules using Ctl-Left mouse click on an atom of one
molecule and fix it: MOE | Edit | Potential | Fix.
Exercise: Flexible Alignment of Opiates (2)
6. Choose MOE | Compute |
Conformations| Flexible Alignment.
Decrease the iteration limit down
to 20, instead of 200.
7. Preserve defaults and press OK
Similarity terms
and weighting
Exercise: Flexible Alignment of Opiates (3)
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!
Exercise: Flexible Alignment of Opiates (4)
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).
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
Descriptor
Filter
Exercise: Sort by Activity
•
Sort in descending order of logBB
1. Open the Sort Database panel (DBV |
Compute | Sort).
2. Select Field: “logBB”
3. Enable “Descending”
4. Press OK
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
Entry Selection is
reflected in the
DBV and the DBV
Plot window
Drag on axis:
Selection Range
Left Click:
Select points
individually
<Shift>
Drag:
<Ctrl>
Drag:
XY
Translate
Plot
Zoom
in/out of
Plot
Drag: Selection
Box
Exercise: Select actives
• Select compounds with logBB > 0
1.
Select active compounds by
using Left mouse drag in
Plot:Display for all entries
where logBB > 0.
2.
Notice selected entries are
updated automatically in the
database viewer
Exercise: Hide Inactives
• Hide all compounds with logBB < 0
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
Exercise: Look at active compounds
1.
Launch database browser by going to (DBV | File | Browser)
2.
Select
Subject:mol (2D)
for depicted
mode
3.
Use forward/backward triangles to
navigate
Exercise: Plot descriptor and activity relationship
1. Show all entries (DBV | Entry | Show All Entries).
2. Start the database correlation plot prompt (DBV | Compute | Analysis |
Correlation Plot…).
3. Pick ‘TPSA’ and ‘logBB’ to
plot along X and Y.
Exercise: Show relationship between all fields
1. Start the database correlation matrix prompt (DBV | Compute | Analysis |
Correlation Matrix…).
2. Press on TPSA/logBB to get same correlation plot
Exercise: Select actives
Select points
in the plot:
Drag:
Selection
Box
Entry Selection is
reflected in both
the DBV and
Correlation Plot
Use the Attributes menu
to change look of 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
Exercise: Show clustering of actives and inactives
1.
2.
3.
4.
5.
6.
7.
Show all entries (DBV | Entry | Show
All Entries)
Open 3D Plot (DBV | Compute |
Analysis | 3D Plot)
Set X to “Weight”, Y to “TPSA”, Z to
“logP(o/w)”
Set activity to “logBB”
Set Threshold to 0
Press Plot
Enlarge points using (MOE | Render |
Ball and Line)
Pharmacophore Overview
Aim: to find chemically unrelated molecules which
share molecular features
1.
Take an active molecule.
2.
Annotate possible
PH4
HB Acceptor
features
Aromatic
3.
Take conformations of a
set of diverse molecules.
4.
Annotate with PH4 features
5.
Find hits which
match the query.
HB Acceptor
3.
Create a query
with these
features
Compute | Conformations | Pharmacophore Elucidation
Objective
Starting 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.
Output database
Activity threshold:
binary or no activity
Selection of Ph4
schemes that can be
stored and loaded
Text report
Ligand database
Specification of
conformational
method
Feature list and
feature properties
Modification of
features / rules
Parameters for
structure alignment
Pharmacophore
search parameters
Exercise: Pharmacophore Elucidation I
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):
1.
2.
3.
4.
5.
Open Elucidator panel in (MOE | Compute |
Conformations | Pharmacophore
Elucidator)
Choose an output database name
(default: ph4elucidate.mdb)
Browse to select as Input Database:
$MOE/sample/mol/1RO6_ligands.mdb
This has 7 ligands from pdb structures
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)
Remain with the default Ph4 scheme (CHD)
and click OK.
Pharmacophore Elucidation II
The output database looks like…
Conformations of
Ph4 alignment
Query features:
D/A = heavy atom Don/Acc
d/a = projected Don/Acc
H = Hyd/Aro
m = Metal
+/- = Cation/Anion
Active
molecules
Separation of
actives/inactives
Accuracy of
actives
Query information
for DB Browser
Alignment
score
Probability
by chance
Accuracy of
inactives
Number of features
of specific type
Total Number
of features
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
SVL is a powerful language designed to allow you to customize MOE and
extend MOE with your own functions
1. Open the SVL
Commands
Window with
(RHS | SVL)
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
7
Press Enter
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 MOE
Text Editor (TED)
Modules & Tasks Manager
ASCII file / SVL program editor
Program control / Source Code
Crash History
Source-level error
trace-back
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
ESTR  wSTR  K 2ij (rij  Lij )  K 3ij (rij  Lij )  K 4ij (rij  Lij )
2
3
4
ij
[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
-
Forcefield File alkane.ff: Angle Bend Block
E ANG  wANG  K 2ij (  O )  K 3ij (  O )  K 4ij (  O )
2
3
4
ijk
[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
Forcefield File alkane.ff: Torsion Block
5

ETOR  wTOR  K N ;ijkl 1  cos(Nijkl )

ijkl N 1
[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
Forcefield File alkane.ff: Electrostatics Block
E ELE  wELE
5
qi q j
e2

d 4 0 i j N 1 (rij  bELE ) k
[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
Forcefield File alkane.ff: VDW Block
EVDW
 (1  a) Rij 
 wVDW   ij 

i j
 rij  aRij 
vdw-scale14
nij
 nij (1  b) Rijmij
mij  nij 



mij
mij
mij 
 mij (rij  bRij )

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
Visualization Setup: Coloring
MOE | Render | Setup…
Set colors
of objects
Press Apply to
institute changes
Restore
defaults
Save new settings
as defaults
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.