Molecular Modeling Workshop - Laboratory for Molecular Simulation

Molecular Modeling Workshop

November 3, 2017 TAMU LMS & HPRC 1

Laboratory for Molecular Simulation (LMS)& High Performance Research Computing (HPRC)

LMS Manager: Dr. Lisa M. Pérez

LMS 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


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 Û Macroscopic

ComputationalChemistry

Molecular ModelingVisualization

InformationScience



Microscopic ó Macroscopic

Quantum MechanicsHY=EY

Molecular Dynamics

F=ma

Mesoscale

Continuum(FEA, CFD)

Ångstroms nm µm mm m

>min

s

µs

ns

ps

fs

Electrons

Atoms

Segments

Grids

Distance

Time

Visualization� 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



Visualization

Images generated in Chimera

Software� 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.



Software – Quantum MechanicsName Description Licensing Price

ABINIT QM (Molecular and Periodic Systems) GNU General Public License, Version 3 Free

AMPAC QM (Semi-empirical) Site License $

CP2K QM, QMD, QM/MM GNU General Public License, Version 3 Free

Dalton QM Specializing in magnetic/electric properties GNU Lesser General Public License, Version 2.1 Free

Discovery Studio QM & MM/MD suite of software with a user-friendly Interface for Life Sciences Floating Licenses $$$

GAMESS-US QM Research Group License Free

Gaussian QM Site License $

Materials Studio MM/MD & QM suite of software with a user-friendly GUI Floating Licenses $$$

MOLPRO QM (specializing in high-level calculations) Site Licenses $$

NWChem QM Educational Community License, Version 2.0 Free

ORCA QM specializing in spectroscopic properties Research Group Academic License Free

PSI4 QM GNU Lesser General Public License version 3 Free

Quantum Espresso QM GNU General Public License Free

Schrödinger QM (Jaguar), QM/MM (Qsite) with a user-friendly GUI Floating Licenses $$$

SIESTA QM specializing in electron transport and Solids GNU General Public License Free

VASP QM specializing in QMD and ultra-soft ECPs Restricted Licenses $$

Software – Molecular Mechanics/DynamicsName Description Licensing Price

AMBER Molecular Mechanics/Dynamics (MM/MD) Site License $

CHARMm MM/MD 8 Floating Licenses $$/$

Desmond MM/MD Site License Free

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 GNU Lesser General Public License (LGPL), version 2.1 Free

LAMMPS MM/MD GNU General Public License Free

Materials Studio MM/MD & QM suite of software with a user-friendly GUI for Materials Sciences Floating Licenses $$$

NAMD MM/MD & more Site License Free

MOE MM/MD – Drug discovery software and more Floating Licenses $$$

Schrödinger MM/MD and more Floating Licenses $$$



Software – Graphical User Interfaces (GUI)Name Description Licensing Price

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

Diamond molecular and crystal structure visualization Chemistry License $$

Gabedit GUI for computational chemistry software Site License Free

iboView Analyze molecular electronic structure, based on Intrinsic Atomic Orbitals (IAOs). Free

Jimp2 GUI for Fenske-Hall (QM) and more Site License Free

Maestro GUI for Schrödinger Suite of Software Token Based License $$$

Molden GUI to visualize results of modeling software Free

Renmol This is a small python script used to make vector graphics of molecules. Free

VMD GUI for NAMD and more Site License Free

Materials Studio by BIOVIABundle Name # of Licenses Modules Included in Bundle

Materials Studio Base 25 VisualizerConformersForcite Plus ParallelGaussian InterfaceQSAR+

MS Pipeline Pilot CollectionReflexVAMP ParallelVAMP Interface

Materials Studio Classical & Mesoscale 1 Adsorption LocatorAmorphous CellBlendsCOMPASS ParallelGULP ParallelGULP Interface

MesociteMesodynMesodyn InterfaceSorptionSynthia

Materials Studio Quantum 3 CASTEP ParallelCASTEP InterfaceDFTB+ ParallelDMOL3 Solid State ParallelDMOL3 Solid State Interface

GULP ParallelGULP InterfaceNMR CASTEP ParallelONETEPQMERAQMERA Interface

1 Equilibria



Discovery Studio by BIOVIABundle Name # of Licenses Modules Included in Bundle

Discovery Studio Base 18 VisualizerAnalysisBiopolymerCatalyst ConformationCatalyst ScoreCDOCKER

CHARMmDMOL3 MolecularMMFF (Force-Field)Protein RefineQUANTUMm (QM/MM)

Discovery Studio Structure Based Design

2 Catalyst DB BuildCatalyst DB SearchCatalyst HypothesisCatalyst SBPCatalyst ShapeCFFDe Novo Evolution

De Novo Ligand BuilderFlexible DockingLibdockLigandFitLigandScoreLUDIMCSS

Discovery Studio Protein 3 ModelerProtein FamiliesProtein Health

Protein DockingSequence AnalysisX-ray analysis (CNX)

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



MOE – Molecular Operating Environment by Chemical Computing Group

LMS holds a 3 Token License

With an option forteaching licenses at no charge.

Computational Chemistry� Quantum Mechanics

� Ab initio - based on first principles� Hartree-FockTheory (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, wB97x-D� and many more

� Semi-empirical� AM1� PM3, PM5, PM7� and many more



Quantum Mechanics� ab initio methods

� Schrödinger Equation� HY=EY ; 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

Quantum Mechanics� Density Functional Theory (DFT)

� Total energy of a system depends only on the electron densityEtot= F[r(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, Jaguar, DMol3, CASTEP, GAMESS-US, NWChem, MOLPRO, orca, Quantum Espresso, and many more



Reaction Mechanism Calculations

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





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

Ru Ru3c2v

2+

Ru Ru4cs

2+

NN N

Ru5c2v

2+

NN N

RuN

NN



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

Ru Ru3c2v

2+ Ru Ru4cs

2+

NN N

Ru5c2v

2+

NN N

RuN

NN

NMR Calculations

Upfield

Downfield

Original assignment for

spectra a)

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



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.

UV/Vis spectra via TD-DFT

Experimental TD-DFT

322+

20



UV/Vis spectra via TD-DFT

Experimental

TD-DFT

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 –1/4Ñ 2 r(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 AnalysisAtoms in Molecules (AIM)



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

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



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

Force Field Terms - Bond Term



Force Field Terms – Angle Term

Force Field Terms -Torsion, Inversion & Coulombic Terms



Force Field Terms – Van der Waals Terms

Force Field Terms –Cross Terms



Class II forcefield(CFF91)

Bond stretching

Angle bending

Torsion Out-of-plane

5-11 Cross Terms

CoulombicVan der Waals

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



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

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).



Force Field Atom Types

CFF/ CFF91/ PCFFcarbonyl functional groups C and O

c_0 carbonyl carbon of aldehydes, ketonesc_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

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=



Minimization� Minimize the potential energy

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

LocalMinima

LocalMinima Local

MinimaGlobalMinimum

Ener

gy

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.



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 <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

Molecular Dynamics� Methods to find the global minimum

� High temperature dynamics� Simulated annealing� Quench dynamics

Time ps

T(K

)

Time ps

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

( ) ( ) ( ) ( )( )ttatattvttv δδδ +++=+21

( ) ( ) ( ) ( )tattvttrttr 2

21δδδ ++=+

( ) ( ) ( ) ( )tattvttrttr 2

21δδδ ++=+

Molecular Dynamics� 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 µs (10-6 s)



Molecular Simulation of ab Initio Protein Folding for a Millisecond Folder NTL9(1−39)

� 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

http://youtu.be/gFcp2Xpd29I

Conformational SearchesIon 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 Å (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 Å (bottom).

Brandon T. Ruotolo, Guido F. Verbeck, Lisa M. Pérez(Thomson), Kent J. Gillig, and David H. Russell J. Am. Chem. Soc., 124, 4214, 2002.



Monte Carlo – RIS Metropolis Monte Carlo

� 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

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



Solvation� 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 e = 1.0� Water e = 78.39� Proteins e = 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

Non-Periodic water simulation (http://www.youtube.com/watch?v=NQhjAtCKghE)

Periodic water simulation (http://www.youtube.com/watch?v=qO956ac-sEE)

Informatics� 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)� Multi-variant mathematical relationship between a set of physico-chemical properties

(descriptors) and a property of interest� Biological activity� Solubility� Mechanical behavior

� 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



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.

Drug Design� de Novo drug design – analog based drug design

� Design ligands to interact with a know receptor



Useful Web Sites� Laboratory for Molecular Simulation

� http://lms.chem.tamu.edu/� Listing of Hardware and Software available through the LMS

� High Performance Research Computing� http://hprc.tamu.edu/

� 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/

Molecular Modeling Workshop - Laboratory for Molecular Simulation

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