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

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, Urbana-Champaign James C. Gumbart Department of Physics Georgia Institute of Technology NIH Hands On Workshop | TCBG | April 20 th , 2017

� � � MD Simulations of Biological Systems Molecular Mechanics Force Fields U = U bonds + U angles + U dihedrals + U vdW + U coulombic bonded non-bonded The CHARMM Force Field Σ k i Σ U = bond ( r i - r 0 ) 2 angles k i angle ( θ i - θ 0 ) 2 + + bonds Σ [ 1 + cos( n i ɸ i + δ i )] dihedrals k i + dihedral i Σ σ ij 12 σ ij 6 i Σ Σ Σ q i q j + - j ≠ i 4 ∈ ij r ij � r ij r ij j ≠ i

Parameter Transferability In Biopolymers Parameter set describes molecular behavior in varied 
 chemical (connectivity) and spatial (conformation) contexts Peptides and Proteins Nucleic Acids H 2 N O NH 2 O S Me O NH N Me N N N HN OH O NH 2 O O O N N H H H N N O N O N N N N N N N H H H O O O O Me O O O O O O Me Me O P O O P O O P O O O NH 2 O O O limited set of isolated 
 R Key Features: building blocks repetitive backbone unit

Parameterization as an Impasse non-standard or 
 small molecule ligands engineered amino acids N HO Me Me HN N N O N Me O S HN N COOH H 2 N COOH O OH H Me O N O S N Tiotropium (Spiriva) Imatinib (Gleevec) cofactors metal centers NH 2 H 2 N NH 2 N O O O O Me Me N S S HS O P O P O N N O N N O O H H O O Fe OH S S O OH O O O P O Coenzyme A NH 2 H 2 N O

General Parameterization Workflow PSF/PDB System Preparation Charges Bonds & Angles PAR File Dihedrals / Torsions K. Vanommeslaeghe et al. , J. Comput. Chem. 2010 , 31, 671-690.

CGenFF Parameterization Workflow Find Missing Parameters PSF/PDB Geometry Optimization (QM) Water Interaction En. (QM) Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) PAR File Torsion Optimization K. Vanommeslaeghe et al. , J. Comput. Chem. 2010 , 31, 671-690.

CGenFF Parameterization Workflow Find Missing Parameters build init PAR PSF/PDB update PDB Geometry Optimization (QM) Water Interaction En. (QM) update PSF Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization update PAR Torsion Scan (QM) PAR File Torsion Optimization update PAR Calculation Action C.G. Mayne et al. , J. Comput. Chem. 2013 , 34, 2757-2270.

ff TK Interface action buttons tasks organized under tabs standard 
 file dialogs action menus

Functionality Provided by ff TK Setup & Perform 
 Multi-dimensional Optimizations Core Functions Abstraction of Gaussian I/O (QM) Assess Performance of Parameters by Visualizing Optimization Data Support Functions • Auto-detect Water Interaction Sites • Visualize Target Data in VMD • Auto-detect Charge Groups • Create Graphic Objects in VMD • Label Atoms in VMD • Auto-detect Non-redundant Torsions • Build & Update Parameter Files • Read Input Parameters from File • Browse Existing Parameter Sets • Read/Write Data From Opt. Logs • Export Plot Data to File • Write Updated Charges to PSF • Reset Opt. Input from Output • Monitor Optimization Progress

ff TK Exemplified by Charge Optimization build init PAR Find Missing Parameters PSF/PDB update PDB Geometry Optimization (QM) Water Interaction En. (QM) update PSF Charge Optimization Hessian Calculation (QM) update PAR Bond & Angle Optimization Torsion Scan (QM) PAR File update PAR Torsion Optimization Calculation Action

Generating Charge Optimization Target Data Load QM optimized geometry | Auto-detect interaction sites | Generat VMD main window ff TK GUI

Generating Charge Optimization Target Data mized geometry | Auto-detect interaction sites | Generate Gaussian Input Files | Run Q Donor Acceptor VMD main window ff TK GUI

Generating Charge Optimization Target Data raction sites | Generate Gaussian Input Files | Run QM | Inspect water optimization Compute water position Optimize 
 distance & rotation ff TK GUI

Generating Charge Optimization Target Data iles | Run QM | Inspect water optimization Visually assess 
 QM-optimized 
 water position(s) ff TK GUI

Charge Optimization Setup Optimization Objective Function Load QM Target Data Prepare Optimization Σ 𝑔 (U MM -U QM ) Optimizer: wat. int. Assign Charges + Compute U MM , d MM , µ MM Σ Compute Objective Function 𝑔 (d MM -d QM ) wat. int. Return Optimized Charges + 𝑔 ( μ MM - μ QM ) Analyze Performance Write Charges to PSF

Assessing MM Water-Interaction Profiles 10 Initial Charges Intermediate Charges 8 Final Optimized Charges Literature Charges � U MM-QM (kcal/mol) 6 4 2 0 -2 -0.4 -0.2 0 0.2 0.4 � d MM-QM (Å)

Sampling MM Water-Interaction Profiles Mode: Simulated Annealing 6 4500 H H H H 5 H N N N N 4000 4 H Δ U MM-QM (kcal/mol) 3 3500 H H 2 3000 Iteration 1 2500 0 2000 -1 -2 1500 -3 1000 -4 500 -5 -6 0 -0.4 -0.2 0 0.2 0.4 -0.4 -0.2 0 0.2 0.4 -0.4 -0.2 0 0.2 0.4 -0.4 -0.2 0 0.2 0.4 Δ d MM-QM ( Å )

Plotting Charge Optimization Data 8 export 7 data 6 Δ E from Target (kcal/mol) 5 4 3 2 1 0 -1 -2 0 50 100 150 200 250 300 Optimization Iteration

ff TK Enables Exciting Science binding 
 mechanisms 
 of inhaled 
 anesthetics with Mark Arcario 
 (Tajkhorshid) mechanism of action for anti-retroviral improved molecular models drugs targeting the HIV capsid from low resolution x-ray data with Abhi Singharoy (Schulten) with Juan Perilla (Schulten)

Starting from Somewhere: CGenFF Output I) preparation of PSF, PDB, 
 and initial PAR files II) use the CGenFF Program for 
 atom typing and “first guess” at 
 missing parameters Me CN t- Bu Me Me

Analyzing QM Dihedral Target Data Torsion Explorer GUI VMD Window

Conclusions Find Missing Parameters Geometry Optimization (QM) Water Interaction En. (QM) Charge Optimization Hessian Calculation (QM) Bond & Angle Optimization Torsion Scan (QM) Torsion Optimization ff TK: - Simplifies the parameterization workflow - Offers opportunity for extensive customization - Provides analytical tools to assess parameter performance www.ks.uiuc.edu/Research/vmd/plugins/fftk

Mayne et al.; J. Comp. Chem. 2013, 34, pp. 2757-2770 (Cover Article) ff TK is available as a VMD Plugin (1.9.2 and greater) Full Documentation and Screencast & Paper Tutorials http://www.ks.uiuc.edu/Research/vmd/plugins/fftk http://www.ks.uiuc.edu/Training/Tutorials/#FFTK May the Force Field Be With You! http://www.ks.uiuc.edu/Highlights/?section=2013&highlight=2013-09 Volume 34 | Issues 31–32 | 2013 Included in this print edition: Issue 31 (December 5, 2013) C OMPUTATIONAL Journal of Issue 32 (December 15, 2013) C HEMISTRY Organic • Inorganic • Physical Biological • Materials Research in Systems Neuroscience www.c-chem.org Questions? Editors: Charles L. Brooks III • Masahiro Ehara • Gernot Frenking • Peter R. Schreiner