1

Laboratory for Molecular Simulation (LMS)

Manager: Dr. Lisa M. Prez
Director: Prof. Michael B. Hall

lms.chem.tamu.edu
mouse@chem.tamu.edu
Office: Rm. 2109 Chemistry (CHAN) phone: 845-9384
Please turn your cell phones to silent for the lecture

March 28, 2014
Molecular Modeling
Workshop
Introduction to Molecular Modeling
! Visualization
! Computational Chemistry
! Quantum Mechanics
! Ab initio
! Density-Functional Theory
! Semi-Empirical
! Classical Mechanics
! molecular mechanic MM
! molecular dynamics MD
! Monte Carlo
! Prediction of properties
! Structural, chemical, physical, biological, etc.
! Understand, explain, and possibly predict chemical processes
! Tools to gain insight at the atomic and molecular level
! Microscopic ! Macroscopic
Computational
Chemistry
Molecular Modeling
Visualization

Information
Science
March 28, 2014
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Microscopic ! Macroscopic
March 28, 2014
Quantum
Mechanics
H"=E"
Molecular
Dynamics
F=ma
Mesoscale
Continuum
(FEA, CFD)
ngstroms nm m mm m
>min

s

s

ns

ps

fs
Electrons
Atoms
Segments
Grids
Distance
Time
Visualization
March 28, 2014
! Building
! Draw in 2-D
! Convert to 3-D
! Rotate
! Rendering
! Line
! Stick
! Ball and Stick
! CPK Ball
! Cartoon
! Surfaces
! Visualizing crystal structures
Maynard, D. and Vigh, G.
Dept. of Chemistry, Texas A&M University
3
Rendered in POV-Ray
Visualization
March 28, 2014
Image generated in Discovery Studio

Software Purchases
March 28, 2014
! The Laboratory for Molecular Simulation currently provides
a wide variety of Commercial and Academic Molecular
Modeling software for students and researchers at Texas A&M
University.
! The LMS assists in the purchase of software that we currently
do not provide. $$$
! The LMS also provides support in the use of Molecular
Modeling software through administration (ie. installation
and updates), training, and scripting.
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Software Quantum Mechanics
March 28, 2014
Name Description Licensing Price
ADF Quantum Mechanics (QM) 8 CPU Floating License $$
ABINIT QM (Molecular and Periodic Systems) Site License* Free
AMPAC QM (Semi-empirical) Site License $
CRYSTAL QM for Periodic Systems Site License $
Dalton QM Specializing in magnetic/electric properties Site License* Free
Discovery Studio QM & MM/MD suite of software with a user-friendly
Interface for Life Sciences
Floating Licenses $$$
GAMESS-US QM Site License* Free
Gaussian QM Site License $
Materials Studio MM/MD & QM suite of software with a user-friendly
GUI for Materials Sciences
Floating Licenses $$$
MOLPRO QM (specializing in high-level calculations) Group Licenses $$
NWChem QM Site License* Free
SIESTA QM specializing in electron transport and Solids Site License* Free
VASP QM specializing in QMD and ultra-soft ECPs 18 Restricted Licenses $$
* Users need to register with the software provider at no charge.
Software Molecular Mechanics/Dynamics
March 28, 2014
Name Description Licensing Price
AMBER Molecular Mechanics/Dynamics (MM/MD) Site License $
CHARMm MM/MD 8 Floating Licenses $$/$
Discovery Studio MM/MD & QM suite of software with a user-friendly
GUI for Life Sciences
Floating Licenses $$$
GROMACS MM/MD specializing in speed and coarse-grained
simulations
Site License* Free
GROMOS MM/MD Group License $
LAMMPS MM/MD Site License* Free
Materials Studio MM/MD & QM suite of software with a user-friendly
GUI for Materials Sciences
Floating Licenses $$$
MOE MM/MD Drug discovery software Floating Licenses

$$$
ICM MM/MD and more Floating or Node locked
Licenses

Free &
$$$
NAMD MM/MD Site License* Free
*
Users need to register with the software provider at no charge.

LMS does not currently hold a license

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Software Graphical User Interfaces (GUI)
March 28, 2014
Name Description Licensing Price
AIM2000 Wavefunction Analysis (Bader Analysis) LMS License $
AGUI (Gaussview) GUI for AMPAC and Gaussian Site License $
AOMix MO analysis & spectra simulation Site License $
Avogadro Visualizer and GUI for many QM and MM codes Site License* Free
Chimera Interactive Visualization and analysis of Molecular
Structures
Site License* Free
ECCE GUI for scientific visualization and computational software Site License* Free
Gabedit GUI for computational chemistry software Site License* Free
gOpenMol GUI for computational chemistry software Site License* Free
Jimp2 GUI for Fenske-Hall (QM) and more Site License* Free
Maestro GUI for Schrdinger Suite of Software Token Based Licnese $$$
Molden GUI to visualize results of modeling software Site License* Free
VMD GUI for NAMD and more Site License* Free
* Users need to register with the software provider at no charge.
Materials Studio by Accelrys
March 28, 2014
Bundle Name # of Licenses Modules Included in Bundle
Materials Studio
Base
25 Visualizer
Conformers
Forcite Plus Parallel
Gaussian Interface
QSAR+
MS Pipeline Pilot Collection
Reflex
VAMP Parallel
VAMP Interface

Materials Studio
Classical &
Mesoscale
1 Adsorption Locator
Amorphous Cell
Blends
COMPASS Parallel
GULP Parallel
GULP Interface
Mesocite
Mesodyn
Mesodyn Interface
Sorption
Synthia

Materials Studio
Quantum
3 CASTEP Parallel
CASTEP Interface
DFTB+ Parallel
DMOL3 Solid State Parallel
DMOL3 Solid State Interface
GULP Parallel
GULP Interface
NMR CASTEP Parallel
ONETEP
QMERA
QMERA Interface
1 Equilibria
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Discovery Studio by Accelrys
March 28, 2014
Bundle Name # of Licenses Modules Included in Bundle
Discovery Studio
Base
18 Visualizer
Analysis
Biopolymer
Catalyst Conformation
Catalyst Score
CDOCKER
CHARMm
DMOL3 Molecular
MMFF (Force-Field)
Protein Refine
QUANTUMm (QM/MM)

Discovery Studio
Structure Based
Design
2 Catalyst DB Build
Catalyst DB Search
Catalyst Hypothesis
Catalyst SBP
Catalyst Shape
CFF
De Novo Evolution
De Novo Ligand Builder
Flexible Docking
Libdock
LigandFit
LigandScore
LUDI
MCSS
Discovery Studio
Protein
3 Modeler
Protein Families
Protein Health
Protein Docking
Sequence Analysis
X-ray analysis (CNX)
Schrdinger
March 28, 2014
Units Items
15 Tokens Glide (5 Tokens) QikProp (2 Tokens)
Liaison (4 Tokens) Canvas (1 Token)
Strike (1 Token) LigPrep (1 Token)
10 Licenses BioLuminate GUI
10 Tokens QSite (4 Tokens) pKa Predictor (3 Tokens)
MacroModel (2 Tokens) Epik (1 Token)
ConfGen (3 Tokens) SiteMap (1 Token)
Jaguar (2 Tokens)
1 License PIPER
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MOE Molecular Operating
Environment by Chemical Computing
Group
March 28, 2014
LMS has a
3 Token License
Computational Chemistry
March 28, 2014
! Quantum Mechanics
! Ab initio - based on first principles
! Hartree-Fock Theory (HF)
! Mller-Plesset Perturbation Theory (MPn ; n = 2, 3, 4, )
! Configuration Interaction (CI ; CIS, CISD, CISDT, )
! Coupled-Cluster (CC ; CCD, CCSD, CCSD(T), CCSD(TQ), )
! Complete Active Space Self Consitent Field (CASSCF)
! Multi-Reference Configuration Interaction (MRCI)
! and many more
! Density Functional Theory
! B3LYP, BP86, B3PW91, mPW1PW91, PBE, M06, TPSS
! and many more
! Semi-empirical
! AM1
! PM3
! PM5
! and many more
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Quantum Mechanics
March 28, 2014
! Ab initio methods
! Schrdinger Equation
! H"=E" ; time-independent Schrdinger equation.
! Applicable to any system, in principle.
! Can model bond breaking and formation
! Used for benchmark values
! Can only be used for small system ( normally < 200 atoms )
! Computationally expensive
! Scaling: Nn n=3, 4, 5, 6,
! Commonly used codes
! Gaussian 09, GAMESS-US, Spartan, NWChem
! Q-Chem, MOLPRO, Dalton, GAMESS-UK, CRYSTAL
! and many more
Quantum Mechanics
March 28, 2014
! Density Functional Theory (DFT)
! Total energy of a system depends only on the electron density
E
tot
= F[$(x,y,z,s)]
! Applicable to any system, in principle.
! Can model bond breaking and formation
! Includes electron correlation with little cost compared to ab initio
methods
! Exact functional is not known
! Commonly used software for DFT
! Gaussian 09, Jaguar, DMol3, Turbomole, Amsterdam Density Functional
(ADF), GAMESS-US, NWChem, MOLPRO, Spartan, GAMESS-UK,
CRYSTAL, and many more
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Reaction Mechanism Calculations
March 28, 2014
Cunxiang Zhao, T. Andrew Mitchell, Ravikrishna Vallakati, Lisa M. Prez, and Daniel Romo
J. Am. Chem. Soc., 2012, 134 (6), pp 30843094
DOI: 10.1021/ja209163w
Reaction Mechanism Calculations
March 28, 2014
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Reaction Mechanism Calculations
March 28, 2014
Quantum Mechanics (ab initio, DFT, Semi-empirical)
Reaction Path Calculations
March 28, 2014
Thomson (Prez), L.M.; Hall, M.B. J. Am. Chem. Soc.2001, 123, 3995.
Calculating transition states is significantly more difficult than
minima.
Experimental data is needed to narrow reaction path possibilities to
be investigated computationally.
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NMR Calculations
March 28, 2014
Upfield
Downfield
Original
assignment for
spectra a)
(E)-2a is
lower in
energy than
(E)-2a-ZnCl
2
Time-Dependant Density Functional Theory
(TDDFT) UV-Vis Spectra
March 28, 2014
Illustrations of the 0.04 contour surface diagram of the B3LYP
calculated HOMOs (upper in each pair) and LUMOs (lower in each
pair) (orbitals involved in the observed UV-vis spectra shown to the
left) for compounds of the type [Mo
2
(DAniF)
3
](O
2
CXCO
2
)
[Mo2DAniF)
3
] and [Mo
2
(DAniF)
3
](O
2
CX) as identified by their
carboxylate anions: oxalate, 6; fumarate, 8; trans,trans-muconate, 12;
tamuate, 13; (E)-pentadienoate, 5; acetylene dicarboxylate, 9;
terephthalate, 15; succinate, 20.
UV-vis spectra of the
series[Mo
2
(aDAniF)
3
]
(O
2
C(CH=CH)nCO
2
)
[Mo
2
DAniF)
3
] (n = 0-4).
Compounds are
identified by the
dicarboxylate linker.
6
8 12
13
UV-vis spectra of
molecules 4 and 5 vs
their linked
counterparts 8 and 12.
8
12
5
4
UV-vis spectra
illustrating the effect
of the degree of
saturation in the series
of molecules
[Mo
2
(DAniF)
3
]
(O
2
CCH
n
CH
n
CO
2
)
[Mo
2
DAniF)
3
], (n = 0,
1, 2).
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8
20
F.A. Cotton, J.P. Donahue, C.A. Murillo, and L.M. Prez, 125, 5486 (2003).
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A) Contour plot of the electron density of [1-F]+ showing the short and long C-F bonds. The
plane was selected to contain the C02, F, and C01 atoms. B) Contour plot of 1/4%
2
$(r) for
[1-F]+ illustrating the covalent nature of the short C-F bond and the dative nature of the long
C-F bond. Positive and negative values are shown with blue solid and red dashed lines,
respectively.
Wavefunction Analysis
Atoms in Molecules (AIM)
March 28, 2014
Quantum Mechanics
March 28, 2014
! Semi-empirical Methods
! AM1, PM3, PM5, PM7, PM7-TM, SAM1, etc.
! Approximate solution to the Schrdinger equation
! Replaces the expensive integrals with parameters
! Applicability is limited by available parameterization
! Heavily used for 1
st
row main group elements
! Limited applicability to transition metals
! Can model bond breaking/formation
! Can model much larger systems than ab initio or DFT
! Commonly used software
! MOPAC 2012, Gaussian 09, Chem3d, AMPAC, VAMP, and many
more
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Molecular Mechanics
March 28, 2014
! Newtons equations
! The potential is approximated by an empirical function
force field that is fitted to approximately reproduce
known interactions
! Applicability is limited by the availability of
parameterization
! Generally, the connectivity of atoms cannot change during
the simulation
! Generally, not suitable for reaction mechanisms
! Can predict relative energies of different conformational states of
material
! And much more
Molecular Mechanics
March 28, 2014
! The molecule is considered to be a collection of atoms held
together by simple elastic or harmonic forces.
! Force Field - A mathematical expression that describes the
dependence of the energy of a molecule on the coordinates of the
atoms in the molecule.
! Force Field Energy Expression:
! E = E
bond
+ E
angle
+ E
torsion
+ E
oop(out-of-plane)
+ E
non-bond
+ E
other
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Force Field Terms
Bond & Angle
Terms
March 28, 2014
Force Field
Terms - Torsion,
Inversion &
Coulombic
Terms
March 28, 2014
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Force
Field
Terms
Van der
Waals
Terms
March 28, 2014
Force Field
Terms
Cross Terms
March 28, 2014
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Class II
forcefield
(CFF91)
Bond stretching
Angle bending
Torsion Out-of-plane
5-11 Cross Terms
Coulombic
Van der Waals
March 28, 2014
Molecular Mechanics
March 28, 2014
! Force Fields differ in their parameters, cross terms and the
method of development
! Class I - simple functional form with data fitted to quantum
mechanical calculations and/or experiment
! Class II - more complicated functional form using cross terms and
data fitted to quantum mechanical calculations and/or experiment
! Class III - new generation force fields that incorporate polarizability
! Rules Based - covers most of the periodic table
! Fundamental quantities are derived for each atom type: electronegativity,
hardness, atomic radius, etc.
! Forcefield parameters are derived at runtime using a series of theoretically or
empirically derived rules
! Specialist - developed for a particular family of compounds
flourinated polymers, zeolites, etc.
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Common Force Fields
March 28, 2014
! MM2/MM3/MM4: Molecular Mechanic Force field for
small organic molecules
! CHARMM: Chemistry at Harvard Macromolecular
Mechanics
! AMBER: Assisted Model Building with Energy Refinement
! OPLS: Optimized Parameters for Liquid Simulation
! CFF: Consistent Force Field
! CVFF: Valence Consistent Force Field
! MMFF94: Merck Molecular Force Field 94
! DREIDING: Generic rules based force field
! UFF: Universal Force Field
UFF Universal Force-Field
March 28, 2014
! The Universal forcefield's atom types are denoted by an element name of one or two
characters followed by up to three other characters:
! The first two characters are the element symbol (i.e., N_ for nitrogen ).
! The third character (if present) represents the hybridization state
! 1 = linear
! 2 = trigonal
! R = an atom involved in resonance
! 3 = tetrahedral
! 4 = square planar
! 5 = trigonal bipyramidal
! 6 = octahedral
! The fourth and fifth characters (if present) indicate characteristics such as
! the oxidation state (i.e., Rh6+3 represents octahedral Rh in the +3 formal oxidation
state
! H___b indicates a diborane bridging hydrogen type
! O_3_z is a framework oxygen type suitable for zeolites).
A. K. Rappe; C. J. Casewit; K. S. Colwell; W. A. Goddard III; W. M. Skiff J. Am. Chem. Soc. 114, 10024-10035
(1992).
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Force Field Atom Types
March 28, 2014
CFF/ CFF91/ PCFF

carbonyl functional groups C and O

c_0 carbonyl carbon of aldehydes, ketones

c_1 carbonyl carbon of acid, ester, amide

c_2 carbonyl carbon of carbamate, urea

cz carbonyl carbon of carbonate

o= oxygen double bonded to O, C, S, N, P

o_1 oxygen in carbonyl group

o_2 ester oxygen

oo oxygen in carbonyl group, carbonate only

oz ester oxygen in carbonate
Atom Types
March 28, 2014
PCFF force field - PCFF was developed based on CFF91 and is intended for
application to polymers and organic materials. It is useful for polycarbonates, melamine
resins, polysaccharides, other polymers, organic and inorganic materials, about 20
inorganic metals, as well as for carbohydrates, lipids, and nucleic acids and also cohesive
energies, mechanical properties, compressibility's, heat capacities, elastic constants. It
handles electron delocalization in aromatic rings by means of a charge library rather than
bond increments.
Cp
nb
hn
s1
Sf
o=
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Minimization
! Minimize the potential energy
E = E
bond
+ E
angle
+ E
torsion
+ E
oop
+ E
nonbond
+ E
other
Local
Minima
Local
Minima
Local
Minima
Global
Minimum
E
n
e
r
g
y

March 28, 2014
Minimization Strategies
March 28, 2014
! Cascade Approach - Smart Minimizer
! Steepest decent
! Max gradient > 100
! Conjugate Gradient
! Max gradient < 100
! Newton
! iterative (pure) Newton-Raphson.
! BFGS (Broyden-Fletcher-Goldfarb-Shanno)
! DFP (Davidon-Fletcher-Powell)
! truncated Newton-Raphson
! Final Convergence
! Many software programs will perform these steps for you,
but some programs you will need to perform this manually.
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Mutations and Minimization
March 28, 2014
Native
Molecular Dynamics
March 28, 2014
! Minimization methods will only optimize your molecule to
the closest local minimum
! Methods to find the global minimum
! Systematic conformational search
! Very time consuming and essentially impossible for anything but the
smallest of molecules
! CH
3
(CH
2
)
n+1
CH
3
! n=1 3 possible configurations <1 sec
! n=2 243 1 min
! n=10 59,049 2 hour
! n=15 14,348,907 100 days
! Molecular Dynamics, Random Sampling, Monte Carlo, Hybrid
Monte Carlo/Dynamics methods
! Samples the potential energy surface by perturbing the geometry
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Molecular Dynamics
March 28, 2014
! Methods to find the global minimum
! High temperature dynamics
! Simulated annealing
! Quench dynamics
Time ps
T
(
K
)

Time ps
E
n
e
r
g
y

Energy supplied to the minimized
structure at the start of the simulation
Simulated Annealing Quench Dynamics
minimize
Molecular Dynamics
! Molecular Dynamics Variations
! Constant Volume - Constant Temperature (NVT)
! Constant Volume - Constant Energy (NVE)
! Constant Pressure Constant Temperature (NPT)
! construct a set of velocities based on the ensemble being used
! Velocities satisfy the Maxwell-Boltzmann distribution
! Each run will start with a different random seed
! Allow atoms to move for one time step
! Calculate the force on the atoms - forcefield
! Calculate the acceleration F=ma
! Calculate the new velocity
! Calculate the new position
! Repeat for as many time steps as desired
( ) ( ) ( ) ( ) ( ) t t a t a t t v t t v ! ! ! + + + = +
2
1
( ) ( ) ( ) ( ) t a t t v t t r t t r
2
2
1
! ! ! + + = +
( ) ( ) ( ) ( ) t a t t v t t r t t r
2
2
1
! ! ! + + = +
March 28, 2014
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Molecular Dynamics
March 28, 2014
! Choosing a time step
! Your time step should be a factor of 10 smaller that the fastest process
in your system.
! Molecular motions such as rotations and vibrations are on the order of 10
-11
-
10
-14
s
! Therefore, a time step of 1 fs (10
-15
s) or less must be used for most
systems.
! You can increase your time step by restricting the fastest processes
! SHAKE or RATTLE algorithms restrict the vibrational motion of the
molecule of interest
! Therefore, a time step of 2-3 fs can be used with the SHAKE or RATTLE
algorithm
! There are some modified shake algorithms that claim they are stable up to
time steps of 8 fs
! Most simulations are on the order of picoseconds (10
-12
s) or
nanoseconds (10
-9
s)
! Protein folding tripzip2 (12-residue protein) folds on the order of
2.5 s (10
-6
s)
Molecular Simulation of ab Initio Protein Folding
for a Millisecond Folder NTL9(1!39)
March 28, 2014
! Vincent A. Voelz, Gregory R. Bowman, Kyle Beauchamp, Vijay S. Pande Journal of the
American Chemical Society 2010 132 (5), 1526-1528
! http://folding.stanford.edu/English/Papers#ntoc6
! Gromacs(GPU version) and Folding@Home were used for the simulations with implicit
solvation
video
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Conformational Searches
March 28, 2014
Ion mobility-mass spectrometry
peptide map of bovine
hemoglobin. Two low-energy
MD calculated structures are
assigned to peptide signals within
the plot: (1) LLGNVLVVVLAR
and (2) LLVVYPWTQR. The
two peptide projections shown
are 15 (top) and 10 (bottom).
Ion mobility-mass
spectrometry peptide map of
horse heart myoglobin. Two
low-energy MD calculated
structures are assignaed to
peptide signals within the plot:
(1) HGTVVLTALGGILK and
(2) VEADIAGHGQEVLIR.
The two peptide projections
shown are 10 (top) and 15
(bottom).
Brandon T. Ruotolo, Guido F. Verbeck, Lisa M.
Prez (Thomson), Kent J. Gillig, and David H.
Russell J. Am. Chem. Soc., 124, 4214, 2002.
Monte Carlo RIS Metropolis Monte Carlo
March 28, 2014
! In outline, an RMMC simulation proceeds as follows:
! Perform an energy minimization on the molecule
! Randomly select a rotatable backbone bond.
! Select a random torsion value for this bond between -180 and
+180 degrees.
! Rotate the bond to its new torsion value and compute the new
energy of the chain.
! Generate a random number, R, between 0 and 1. If
exp
[-(Enew -Eold)/kT]
> R, keep the new torsion value. Otherwise,
restore the old value.
! Repeat until the desired number of iterations has been
performed
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Molecular Dynamics Steps
March 28, 2014
! Prepare the Molecule
! Minimization
! Required!!!!!!
! Heating
! Raise the temperature of the system from 0oC to the desired
temperature.
! Many programs/researchers skip this step
! Equilibration
! Ensure that the system is stable (NVE)
! Production
! Run simulation to collect pertinent data
! NVT, NVE, NPT, etc
Solvation
March 28, 2014
! Explicit Solvation
! Very expensive
! Solvent molecules tend to boil off
! Need to use a periodic system to prevent loss of solvent
molecules
! Solvent Dielectric Models
! Treat the solvent as a bulk property
! Vacuum & = 1.0
! Water & = 78.39
! Proteins & = 4.0
! Constant dielectric constant
! Distance Dependent Dielectric Models
! Dielectric constant varies with the distance between the charged
species
! Generally used for large systems and proteins
Water simulation
Periodic water simulation
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Informatics
March 28, 2014
! Storage and retrieval of information
! Databases
! Structures
! Properties
! Activities
! Combinatorial Chemistry
! Protein Bioinformatics
! Drug Design
! Catalysis
! QSAR Quantitative Structure Activity Relationships
Quantitative Structure Activity Relationship (QSAR)
March 28, 2014
! Multi-variant mathematical relationship between a set of
physico-chemical properties (descriptors) and a property of
interest
! Biological activity
! Solubility
! Mechanical behavior
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! Utilizes structure and sequence similarities for predicting unknown
protein structures.
! Database comparison
! Molecular mechanics/
dynamics
! NMR constraints
! Web resource: http://zhanglab.ccmb.med.umich.edu/I-TASSER/
Homology
March 28, 2014
Drug Design
! Generate a pharmacophore based on a set of known
biologically active molecules.
! Use the pharmacophore to search a database for other
potentially active molecules.
March 28, 2014
27
Drug Design
March 28, 2014
! de Novo drug design analog based drug design
! Design ligands to interact with a know receptor
Useful Web Sites
March 28, 2014
! Laboratory for Molecular Simulation
! http://lms.chem.tamu.edu/
! Listing of Hardware and Software available through the LMS
! Accelrys Inc.
! http://www.accelrys.com/
! Chemical Computing Group, Inc.
! http://www.chemcomp.com/software.htm
! MOE Molecular Operating Environment
! Schrdinger Inc.
! http://www.schrodinger.com/
! http://www.schrodinger.com/supporttraining/18/
! Support videos
! Tripos, Inc.
! http://www.tripos.com/
! SYBYL software
! Gaussian, Inc.
! http://www.gaussian.com/