Molecular Modeling Workshop

Molecular Modeling Workshop Laboratory for Molecular Simulation (LMS) Manager: Dr. Lisa M. Pérez Director: Prof. Michael B. Hall lms.chem.tamu.edu [email protected] Office: Rm. 2109 Chemistry (CHAN)

phone: 845-9384

Please sign in and turn your cell phones to silent for the lecture February 19, 2016

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

Molecular Modeling Visualization

Computational Chemistry

Information

Science

—  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 February 19, 2016

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Molecular Modeling Workshop

Microscopic ó Macroscopic Time

Grids

>min

Continuum (FEA, CFD)

Segments

s µs

Atoms

ns Electrons

ps fs

Quantum Mechanics HΨ=EΨ

Mesoscale

Molecular Dynamics F=ma

Ångstroms

nm

µm

mm

m

Distance February 19, 2016

Visualization —  Building —  Draw in 2-D —  Convert to 3-D —  Rotate

—  Rendering —  Line —  Stick —  Ball and Stick —  CPK Ball —  Cartoon

Maynard, D. and Vigh, G. Dept. of Chemistry, Texas A&M University

—  Surfaces

—  Visualizing crystal structures February 19, 2016

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Molecular Modeling Workshop

Visualization

Images generated in Chimera

February 19, 2016

Software Purchases —  The Laboratory for Molecular Simulation currently provides

a wide variety of academic licenses for 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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Molecular Modeling Workshop

Software – Quantum Mechanics 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

ORCA

QM specializing in spectroscopic properties

Site License*

Free

SIESTA

QM specializing in electron transport and Solids

Site License*

Free

VASP

QM specializing in QMD and ultra-soft ECPs

Restricted Licenses

$$

* Users need to register with the software provider at no charge. February 19, 2016

Software – Molecular Mechanics/Dynamics 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 & $$$

Schrödinger

MM/MD and more

Floating Licenses

$$$

NAMD

MM/MD

Site License*

Free

* Users § LMS

need to register with the software provider at no charge. does not currently hold a license

Laboratory for Molecular Simulation, Texas A&M University

February 19, 2016

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Molecular Modeling Workshop

Software – Graphical User Interfaces (GUI) 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

Chemmisian

GUI for the analysis of electronic structure and spectra.

Site License*

$

Chimera

Interactive Visualization and analysis of Molecular Structures

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 Schrödinger 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.

February 19, 2016

Materials Studio by BIOVIA Bundle Name

# of Licenses

Materials Studio Base

25

Visualizer Conformers Forcite Plus Parallel Gaussian Interface QSAR+

Modules Included in Bundle 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 February 19, 2016

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Molecular Modeling Workshop

Discovery Studio by BIOVIA 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) February 19, 2016

Schrödinger 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)

Prime (8 Tokens)

1 License

PIPER

February 19, 2016

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Molecular Modeling Workshop

MOE – Molecular Operating Environment by Chemical Computing Group LMS holds a 3 Token License

With an option for teaching licenses at no charge. February 19, 2016

Computational Chemistry —  Quantum Mechanics —  Ab initio - based on first principles —  Hartree-Fock Theory (HF) —  Møller-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, ωB97x-D —  and many more —  Semi-empirical —  AM1 —  PM3, PM5, PM7 —  and many more February 19, 2016

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Quantum Mechanics —  Ab initio methods —  Schrödinger Equation —  HΨ=EΨ ; time-independent Schrödinger 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=2, 3, 4, 5, 6, … —  Commonly used codes —  Gaussian 09, GAMESS-US, Spartan, NWChem —  Q-Chem, MOLPRO, Dalton, GAMESS-UK, CRYSTAL —  and many more February 19, 2016

Quantum Mechanics —  Density Functional Theory (DFT) —  Total energy of a system depends only on the electron density Etot= F[ρ(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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Molecular Modeling Workshop

Reaction Mechanism Calculations

Cunxiang Zhao, T. Andrew Mitchell, Ravikrishna Vallakati, Lisa M. Pérez, and Daniel Romo J. Am. Chem. Soc., 2012, 134 (6), pp 3084–3094 DOI: 10.1021/ja209163w February 19, 2016

Reaction Mechanism Calculations

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Molecular Modeling Workshop

Reaction Mechanism Calculations

February 19, 2016

3 + 6Acetonitrile ➛ 4 + 3Acetonitrile ➛ 5 + Naphthalene

2+

Ru

3 c2v

Ru

2+

5 c2v

Ru N

N

N

Ru N N

N

2+

Ru

4 cs

Ru N N

N

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Molecular Modeling Workshop

NMR Calculations Original assignment for spectra a)

Upfield Downfield

(E)-2a is lower in energy than (E)-2a-ZnCl2

February 19, 2016

Quantum Mechanics – (ab initio, DFT, Semi-empirical) Reaction Path Calculations

Thomson (Pérez), 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. February 19, 2016

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Molecular Modeling Workshop

3 + 6Acetonitrile ➛ 4 + 3Acetonitrile ➛ 5 + Naphthalene

2+

2+

Ru

4 cs

Ru N N

Ru

3 c2v

N

Ru

2+

5 c2v

Ru N N

N

Ru N N

N

February 19, 2016

UV/Vis spectra via TD-DFT Experimental

TD-DFT

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Molecular Modeling Workshop

UV/Vis spectra via TD-DFT Experimental

TD-DFT

February 19, 2016

Wavefunction Analysis Atoms in Molecules (AIM)

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 ρ(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. February 19, 2016

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Molecular Modeling Workshop

Quantum Mechanics —  Semi-empirical Methods —  AM1, PM3, PM5, PM7, PM7-TM, SAM1, etc. —  Approximate solution to the Schrödinger equation —  Replaces the expensive integrals with parameters —  Applicability is limited by available parameterization —  Mostly used for 1st 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 February 19, 2016

Molecular Mechanics —  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 February 19, 2016

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Molecular Modeling Workshop

Molecular Mechanics —  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 = Ebond + Eangle + Etorsion + Eoop(out-of-plane) + Enon-bond + Eother

February 19, 2016

Force Field Terms - Bond Term

February 19, 2016

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Molecular Modeling Workshop

Force Field Terms – Angle Term

February 19, 2016

Force Field Terms - Torsion, Inversion & Coulombic Terms

February 19, 2016

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Molecular Modeling Workshop

Force Field Terms – Van der Waals Terms

February 19, 2016

Force Field Terms – Cross Terms

February 19, 2016

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Molecular Modeling Workshop

Class II forcefield (CFF91)

Bond stretching

Angle bending

Torsion

Out-of-plane

5-11 Cross Terms

Coulombic

Van der Waals February 19, 2016

Molecular Mechanics —  Force Fields differ in their parameters, terms and the method of

development

—  Class I - simple functional form with data fitted to quantum mechanical

calculations and/or experiment (AMBER, CHARMM, etc)

—  Class II - more complicated functional form using cross terms and data

fitted to quantum mechanical calculations and/or experiment (CFF, PCFF, etc) —  Class III - new generation force fields that incorporate polarizability (AMOEBA, AMBER ff02, CHARMM Drude, etc) —  Rules Based - covers most of the periodic table – UFF, DREIDING, etc

—  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.

—  Reaction Forcefields - ReaxFF

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Molecular Modeling Workshop

Common Force Fields —  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 —  ReaxFF: Speciality force-field to allow bond breaking February 19, 2016

UFF – Universal Force-Field —  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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Molecular Modeling Workshop

Force Field Atom Types 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 February 19, 2016

Atom Types

o= hn Sf Cp

nb s1

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. February 19, 2016

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Molecular Modeling Workshop

Minimization —  Minimize the potential energy

Energy

E = Ebond + Eangle + Etorsion + Eoop + Enonbond + Eother

Local Minima Local Minima Global Minimum

Local Minima

February 19, 2016

Minimization Strategies —  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. February 19, 2016

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Molecular Modeling Workshop

Mutations and Minimization

Native

February 19, 2016

Molecular Dynamics —  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 —  CH3(CH2)n+1CH3 —  n=1 3 possible configurations 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 Modeling Workshop

Molecular Dynamics Steps —  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 February 19, 2016

Solvation —  Explicit Solvation —  Very expensive —  Solvent molecules tend to boil off Non-Periodic water simulation —  Need to use a periodic system to prevent loss of solvent

molecules

Periodic water simulation

—  Solvent Dielectric Models —  Treat the solvent as a bulk property —  Vacuum ε = 1.0 —  Water ε = 78.39 —  Proteins ε = 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 February 19, 2016

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Molecular Modeling Workshop

Informatics —  Storage and retrieval of information —  Databases —  Structures —  Properties —  Activities

—  Combinatorial Chemistry —  Protein Bioinformatics —  Drug Design —  Catalysis —  QSAR – Quantitative Structure Activity Relationships

February 19, 2016

Quantitative Structure Activity Relationship (QSAR) —  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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Molecular Modeling Workshop

Homology —  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/ February 19, 2016

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.

February 19, 2016

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Molecular Modeling Workshop

Drug Design —  de Novo drug design – analog based drug design —  Design ligands to interact with a know receptor

February 19, 2016

Useful Web Sites —  Laboratory for Molecular Simulation —  http://lms.chem.tamu.edu/ —  Listing of Hardware and Software available through the LMS

—  BIOVIA, Inc. —  http://www.accelrys.com/

—  Chemical Computing Group, Inc. —  http://www.chemcomp.com/software.htm —  MOE – Molecular Operating Environment

—  Schrödinger Inc. —  http://www.schrodinger.com/ —  http://www.schrodinger.com/videos —  Support videos

—  Gaussian, Inc. —  http://www.gaussian.com/ February 19, 2016

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