The Force Field Toolkit ( ff TK) Christopher G. Mayne, Emad - - PowerPoint PPT Presentation

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The Force Field Toolkit ( ff TK) Christopher G. Mayne, Emad - - PowerPoint PPT Presentation

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Parameterizing Small Molecules Using: The Force Field Toolkit ( ff TK) Christopher G. Mayne, Emad Tajkhorshid NIH Center for Macromolecular Modeling and Bioinformatics Beckman Institute for Advanced Science and Technology University of Illinois,

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SLIDE 1

The Force Field Toolkit (ffTK)

Christopher G. Mayne, Emad Tajkhorshid

NIH Center for Macromolecular Modeling and Bioinformatics Beckman Institute for Advanced Science and Technology University of Illinois, Urbana-Champaign

Parameterizing Small Molecules Using:

James C. Gumbart

Department of Physics Georgia Institute of Technology

NIH Hands On Workshop | TCBG | April 20th, 2017

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SLIDE 2

Σ ki

(ri - r0 )2

bonds bond

Σ

( θi - θ0 )2

angles ki

angle

Σ

[1 + cos( niɸi + δi )]

dihedralski

dihedral

Σ

i Σ j≠i 4∈ij

  • σij

rij

12

σij rij

6

  • Σ

i Σ j≠i

qiqj rij U = + + + +

MD Simulations of Biological Systems

U = Ubonds Uangles Udihedrals UvdW Ucoulombic + + + + bonded non-bonded

Molecular Mechanics Force Fields

The CHARMM Force Field

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SLIDE 3

Parameter Transferability In Biopolymers

O O P O O O O O O P O O O O O N N N N O NH2 N N NH O NH2 HN O O Me P O O O O N N N N H2N

Parameter set describes molecular behavior in varied
 chemical (connectivity) and spatial (conformation) contexts

Peptides and Proteins Nucleic Acids repetitive backbone unit limited set of isolated
 building blocks

R Key Features:

H N N H H N N H H N N H Me O O O O O O NH2 O Me Me OH O O S Me

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SLIDE 4

Parameterization as an Impasse

N O HN N HN Me Me N N N N O Me Me O O OH S S

Imatinib (Gleevec) Tiotropium (Spiriva)

H2N COOH O

N H COOH HO

non-standard or
 engineered amino acids small molecule ligands cofactors metal centers

Coenzyme A

O N O OH P O O O N N N NH2 O P O O O P O O O N H N H Me Me OH O O HS

H2N O S NH2 O S S H2N O S NH2 O Fe

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SLIDE 5

System Preparation Charges Bonds & Angles Dihedrals / Torsions

General Parameterization Workflow

PSF/PDB PAR File

  • K. Vanommeslaeghe et al., J. Comput. Chem. 2010, 31, 671-690.
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SLIDE 6

CGenFF Parameterization Workflow

Water Interaction En. (QM) Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) Torsion Optimization Find Missing Parameters Geometry Optimization (QM)

PSF/PDB PAR File

  • K. Vanommeslaeghe et al., J. Comput. Chem. 2010, 31, 671-690.
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SLIDE 7

CGenFF Parameterization Workflow

Water Interaction En. (QM) Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) Torsion Optimization Find Missing Parameters Geometry Optimization (QM) update PSF update PAR update PAR build init PAR update PDB

PSF/PDB PAR File Calculation Action

C.G. Mayne et al., J. Comput. Chem. 2013, 34, 2757-2270.

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SLIDE 8

action buttons action menus standard
 file dialogs

ffTK Interface

tasks organized under tabs

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SLIDE 9

Functionality Provided by ffTK

Core Functions Support Functions

Assess Performance of Parameters by Visualizing Optimization Data Setup & Perform
 Multi-dimensional Optimizations Abstraction of Gaussian I/O (QM)

  • Auto-detect Water Interaction Sites
  • Auto-detect Charge Groups
  • Auto-detect Non-redundant Torsions
  • Build & Update Parameter Files
  • Browse Existing Parameter Sets
  • Write Updated Charges to PSF
  • Reset Opt. Input from Output
  • Visualize Target Data in VMD
  • Create Graphic Objects in VMD
  • Label Atoms in VMD
  • Read Input Parameters from File
  • Read/Write Data From Opt. Logs
  • Export Plot Data to File
  • Monitor Optimization Progress
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SLIDE 10

update PSF update PAR update PAR build init PAR update PDB

Calculation Action

ffTK Exemplified by Charge Optimization

Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) Torsion Optimization Find Missing Parameters Geometry Optimization (QM)

PSF/PDB PAR File

Water Interaction En. (QM) Charge Optimization

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SLIDE 11

Generating Charge Optimization Target Data

Load QM optimized geometry | Auto-detect interaction sites | Generat

VMD main window ffTK GUI

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SLIDE 12

Generating Charge Optimization Target Data

mized geometry | Auto-detect interaction sites | Generate Gaussian Input Files | Run Q

Acceptor Donor

VMD main window ffTK GUI

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SLIDE 13

Generating Charge Optimization Target Data

raction sites | Generate Gaussian Input Files | Run QM | Inspect water optimization

Compute water position Optimize
 distance & rotation

ffTK GUI

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SLIDE 14

Generating Charge Optimization Target Data

iles | Run QM | Inspect water optimization

Visually assess
 QM-optimized
 water position(s)

ffTK GUI

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SLIDE 15

Charge Optimization

Load QM Target Data Prepare Optimization Optimizer: Assign Charges Compute UMM, dMM, µMM Compute Objective Function Return Optimized Charges Analyze Performance Write Charges to PSF Setup Optimization

𝑔(UMM-UQM) 𝑔(dMM-dQM) 𝑔(μMM-μQM) Objective Function +

Σ

  • wat. int.

Σ

  • wat. int.

+

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SLIDE 16
  • 0.4
  • 0.2

0.2 0.4

dMM-QM (Å)

  • 2

2 4 6 8 10

UMM-QM (kcal/mol)

Initial Charges Intermediate Charges Final Optimized Charges Literature Charges

Assessing MM Water-Interaction Profiles

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SLIDE 17
  • 0.4 -0.2

0.2 0.4

  • 6
  • 5
  • 4
  • 3
  • 2
  • 1

1 2 3 4 5 6

  • 0.4 -0.2

0.2 0.4 -0.4 -0.2 0.2 0.4 -0.4 -0.2 0.2 0.4 500 1000 1500 2000 2500 3000 3500 4000 4500

Sampling MM Water-Interaction Profiles

N H N H N H H H N H H H

ΔdMM-QM (Å) ΔUMM-QM (kcal/mol) Iteration Mode: Simulated Annealing

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SLIDE 18

50 100 150 200 250 300

Optimization Iteration

  • 2
  • 1

1 2 3 4 5 6 7 8

ΔE from Target (kcal/mol)

Plotting Charge Optimization Data

export data

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SLIDE 19

ffTK Enables Exciting Science

binding
 mechanisms


  • f

inhaled
 anesthetics improved molecular models from low resolution x-ray data

with Mark Arcario
 (Tajkhorshid) with Juan Perilla (Schulten)

mechanism of action for anti-retroviral drugs targeting the HIV capsid

with Abhi Singharoy (Schulten)

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SLIDE 20

Me t-Bu CN Me Me

I) preparation of PSF, PDB,
 and initial PAR files II) use the CGenFF Program for
 atom typing and “first guess” at 
 missing parameters

Starting from Somewhere: CGenFF Output

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SLIDE 21

Analyzing QM Dihedral Target Data

VMD Window Torsion Explorer GUI

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SLIDE 22

Conclusions

Water Interaction En. (QM) Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) Torsion Optimization Find Missing Parameters Geometry Optimization (QM)

  • Simplifies the parameterization workflow
  • Offers opportunity for extensive customization
  • Provides analytical tools to assess parameter performance

www.ks.uiuc.edu/Research/vmd/plugins/fftk ffTK:

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SLIDE 23

ffTK is available as a VMD Plugin (1.9.2 and greater) Mayne et al.; J. Comp. Chem. 2013, 34, pp. 2757-2770 (Cover Article) Full Documentation and Screencast & Paper Tutorials

http://www.ks.uiuc.edu/Research/vmd/plugins/fftk http://www.ks.uiuc.edu/Training/Tutorials/#FFTK

Volume 34 | Issues 31–32 | 2013 Included in this print edition: Issue 31 (December 5, 2013) Issue 32 (December 15, 2013)

Research in Systems Neuroscience

www.c-chem.org

COMPUTATIONAL

Journal of

CHEMISTRY

Organic • Inorganic • Physical Biological • Materials

Editors: Charles L. Brooks III • Masahiro Ehara • Gernot Frenking • Peter R. Schreiner

May the Force Field Be With You!

http://www.ks.uiuc.edu/Highlights/?section=2013&highlight=2013-09

Questions?