dipesh risal, ph. d. life sciences product manager june 26...
TRANSCRIPT
Towards Increased Accuracy in
Computational Drug Discovery with QM/MM
Towards Increased Accuracy in
Computational Drug Discovery with QM/MM
This presentation and/or any related documents contains statements regarding our plans or expectations for future features, enhancements or functionalities of current or future products (collectively "Enhancements"). Our plans or expectations are subject to change at any time at our discretion. Accordingly, Accelrys is making no representation, undertaking no commitment or legal obligation to create, develop or license any product or Enhancements. The presentation, documents or any related statements are not intended to, nor shall, create any legal obligation upon Accelrys, and shall not be relied upon in purchasing any product. Any such obligation shall only result from a written agreement executed by both parties. In addition, information disclosed in this presentation and related documents, whether oral or written, is confidential or proprietary information of Accelrys. It shall be used only for the purpose of furthering our business relationship, and shall not be disclosed to third parties.
Dipesh Risal, Ph. D.Life Sciences Product ManagerJune 26, 2008
Dipesh Risal, Ph. D.Life Sciences Product ManagerJune 26, 2008
2© 2007 Accelrys, Inc.
OverviewOverview
• QM/MM background• QM/MM implementation• Validation: Scientific applications of QM/MM
3© 2007 Accelrys, Inc.
QM/MM overviewQM/MM overview
• Combine QM and MM methods to achieve good accuracy at low cost– Treat ‘chemically
significant’ region with QM– Treat the bulk with MM– Combine the results
QM region
MM region
Ligand
4© 2007 Accelrys, Inc.
QM/MM in Discovery StudioQM/MM in Discovery Studio
• A QM/MM method has been implemented that incorporates– DMol3 (DFT) for the QM
region– CHARMm for the MM region– QUANTUMm, a
communication program between the two regions
• How do each of these programs work?
QM region
MM region
Ligand
5© 2007 Accelrys, Inc.
QM/MM OverviewQM/MM Overview
Anatomy of QM/MM machinery
• QM and MM servers only provide energies and gradients• Propagation algorithms (geometry optimization, MD, TS search ...) operate on data received from compute engines
QM/MM Driver
QM Engine
xyzE∇Eq
QM/MM Driver
MM Engine
xyzq
E∇E
QM/MM Driver
Call QM Call MMGeometry
optimization or MD step
Repeat
6© 2007 Accelrys, Inc.
DMol3 OverviewDMol3 Overview
• DMol3 uses DFT to predict structures, energies, electronic properties
• Works for molecular and periodic systems• Extremely fast
– Numerical basis sets provide a rapid means of evaluating Coulomb and exchange-correlation potentials
– Provides options to trade off between computational cost and accuracy
• Delley, J. Chem. Phys.113, 7756 (2000)– Energy calculations on drug-size molecules require few
minutes on typical laptop
7© 2007 Accelrys, Inc.
DMol3 FunctionalsDMol3 Functionals
H-bonded complexes Dispersion-dominatedcomplexes
Mixedcomplexes
Type of complex DMol3/PBE DMol3/HCTH Z-T B3LYP1 Z-T PBE1
H-bond 1.0 3.4 2.0 1.3
Dispersion 3.2 2.8 6.5 4.9
Mixed 1.2 0.9 2.9 1.9
Avg. Error (kcal/mol) of binding energies in loose complexes
1. J. Chem. Theory Comput. (2007), 3, 289-300.
8© 2007 Accelrys, Inc.
MM engine: CHARMmMM engine: CHARMm
• CHARMm: the industry standard for simulation of macromolecules and protein-ligand systems• Constant Forcefield development
– Alex MacKerell, Charlie Brooks, Bernard Brooks, Accelrys, Others• Most comprehensive simulation package available
– MM, MD– CDOCKER– Free Energy Perturbation (FEP)– MM-PB/GB SA Scoring– Normal Mode analysis– RDOCK (refinement of Protein-Protein docking)– ChiRotor, Looper– Replica Exchange Molecular Dynamics (REMD)– Three implicit membrane models
• GBSW, GBSA-IM, IMM1
– Umbrella sampling– Monte Carol simulations– Physics-based pK Prediction and Protein Ionization– Constant-pH MD– And many more!
• Strong UI support in Discovery Studio– Antibody Modeling– Implicit Membrane Modeling – Receptor-Flexible Docking
9© 2007 Accelrys, Inc.
QUANTUMm OverviewQUANTUMm Overview
• Scientific requirements for biological QM/MM:– QM region “feels” MM atom
environment– Minimal number of FF parameters
for QM region• Issues to address
– Embedding: how does the QM region interact with the MM region?
– Boundary region: what happens to bonds that cross between regions?
),( QMMMtotal RREE =
• Total energy ...
)()()(),( / IOEIEOEIOE MMQMQMMMtotal ↔++=
10© 2007 Accelrys, Inc.
QM ↔ MM Coupling: ElectrostaticsQM ↔ MM Coupling: Electrostatics
MM → QM
QM → MM
QM density is polarized by MM point charges:electronic embedding
O charges polarize I density
I gradients induce forces on O
Part of QM energy expressionelecMMQME /
11© 2007 Accelrys, Inc.
QUANTUMm Issue: Broken QM ↔ MM bondsQUANTUMm Issue: Broken QM ↔ MM bonds
→
add link atom (L) to QM calculation
Problem: QM calculation on I region yields unrealistic species
• Link atom is absent in MM calculation• Position restrained onto CA -CB vector• QM/MM server program handles link atoms transparently
[Field, JCC 1990]
12© 2007 Accelrys, Inc.
Complications: ElectrostaticsComplications: Electrostatics
Electronic embedding and link atoms
Problem: QM overpolarization near link atoms: MM host too close
Solution: the QM fragment should see no charge from MM host atom
[Bakowies, JPC 1996; Sinclair, J Chem Soc Faraday 1998]
13© 2007 Accelrys, Inc.
QUANTUMm User InterfaceQUANTUMm User Interface
• DS QUANTUMm allows easy job setup • Select QM region• Set DFT options
– Charge on QM region– Spin multiplicity of QM region– Relative precision (basis set, integration grid, SCF
convergence)
• Number of processors for parallel calculation• Provides the tools you need to balance the size of the
problem, relative accuracy, and computational cost
14© 2007 Accelrys, Inc.
QM/MM Implementation IQM/MM Implementation I
• Methods available for first release– QM/MM Minimization – QM/MM Energy Calculation (Single Point Energy)
• If only the ligand is in the QM region, both protocols output ESP, Hirshfeld and Mulliken charges for ligand
– Recharge Ligand Pipeline Pilot Component• Point charges from a protein model used in the electronic
structure calculation, causing polarization of the ligand
15© 2007 Accelrys, Inc.
QM/MM Calculation: Setup in Discovery StudioQM/MM Calculation: Setup in Discovery Studio
16© 2007 Accelrys, Inc.
QM/MM Applications for Life Science QM/MM Applications for Life Science
• QM/MM-derived ligand partial charges for:– improved docking accuracy (and simulation)
• Optimization of hydrogen bonds – Post-processing of docked poses
• Modeling of special electrostatic interactions not fully captured by force fields
– Cation-Pi interactions– Pi-Pi interactions– Charge transfer – Metal-ligand-protein interactions
• Improved estimate of interaction energy between protein and ligand
• QM/MM in conjunction with MD1, QM-PBSA2
• Preparing ligands and cofactors for MM calculations3
– Heme, others
• Studying reaction mechanisms3
– individual steps (hydrolysis, etc.)– transition state– entire catalytic cycle
• Activation free energy3
• QM/MD (dynamics)• Semi-empirical method in QM/MM
1. J Comput Aided Mol Des. 2007 Jan-Mar;21(1-3):131-72. J Phys Chem B, 109 (2):10474-83. 3. Chem Rev. 2006 Sep;106(9):3497-5194. Drug Discov Today: Technologies, 2004 Dec; 1(3), 253-2605. Drug Discov Today. 2007 Sep;12(17-18):725-31 .
Possible Today. Some validationAlready available
Possible Today. Validation ongoing
Possible in future releases based on customer prioritization
17© 2007 Accelrys, Inc.
QM/MM Background: Partial Charge AnalysisQM/MM Background: Partial Charge Analysis
MM Min QM/MM Min
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
C11 O11 O12 C10 C9 C8 C7 C2 S1 C6 C5 N1 C3 O3 N2 C4 H1 H2 H3 H4 H5 H6 H7 H8 H9H10 H11 H12 H13 H14 H15 H16
CHARMm M-Rone
CFF
QM/MM Min
Generally, H-bond donors become increase in δ+H-bond acceptors increase in δ-
Partial charges on ligand after MM and QM/MM Minimization, 1STP-1: Streptavidin/Biotin
18© 2007 Accelrys, Inc.
QM/MM Applications: BackgroundQM/MM Applications: Background
• CDOCKER is a CHARMm-based small molecule docking refinement algorithm1
– Uses soft-core potentials– Grid-based (optional)
1. Wu et al. J Comput Chem (2003) 24:1549-62
Generate ligand conformationsthrough high temperature MD
(grid-based) simulated annealing
Full minimization
Output # of refined ligand posessorted by energy
(vdW+ e/s + ligand strain)
Random (rigid-body) rotation
19© 2007 Accelrys, Inc.
QM/MM Applications: Improving Docking Accuracy*QM/MM Applications: Improving Docking Accuracy*
• CDOCKER on AstexDiverse Dataset** (85 diverse, high-resolution protein-ligand complexes)
Top Pose
Dock with CDOCKER
CDOCKER
Calculate RMSD to X-ray
Prepared X-rayProtein- Ligand Complex
CDOCKER-QM-CDOCKER
Calculate QM charges for ligand
CDOCKER
Top Pose
Dock with CDOCKER
Calculate RMSD to X-ray
Top Pose
Randomize Ligand Conformation
1.02891.6331Avg.RMSD
88.10%72.62%Success
Best Pose
First Pose
X-Ray (A)
1.01.6 Avg.RMSD
88%73%Success
Best Pose
First Pose
X-Ray (A)
1.02891.6331Avg.RMSD
88.10%72.62%Success
Best Pose
First Pose
X-Ray (A)
1.01.6 Avg.RMSD
88%73%Success
Best Pose
First Pose
X-Ray (A)
0.91141.3856Avg.RMSD
90.48%77.38%Success
Best Pose
First Pose
X-Ray (B)
1.31.4Avg.RMSD
88%79%Success
Best Pose
First Pose
X-Ray (B)
* Cho et al, J Comput Chem 26: 915–931, 2005 ** Hartshorn et al. JMC 2007
Poses are scored with CDOCKER Energy: sum of electrostatics+vdW interaction energy + ligand strain E
20© 2007 Accelrys, Inc.
QM/MM Applications: Improving Docking AccuracyQM/MM Applications: Improving Docking Accuracy
•
Available options: ESP, Hirshfeld, Mulliken
Available Options: Coarse/Medium/Fine.Affects the basis set, k-point, and SCF convergence criteria
Available Options: local (LDA) potentials (PWC, VWN) and gradient- corrected (GGA) potentials (PW91, BP, PBE, BLYP, BOP, VWN-BP, RPBE, HCTH).
• Pipeline Pilot workflow for CDOCKER-QM-CDOCKER
21© 2007 Accelrys, Inc.
QM/MM Applications: Improving Docking AccuracyQM/MM Applications: Improving Docking Accuracy
• CDOCKER-QM-CDOCKER on AstexDiverse dataset: success by RMSD bin
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
< 0.5 Å < 1.0 Å < 1.5 Å < 2.0 Å
CDOCKER First PoseQM-CDOCKER First Pose
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
< 0.5 Å < 1.0 Å < 1.5 Å < 2.0 Å
CDOCKER Best PoseQM-CDOCKER Best
Only single, top-rankedpose for each PDB complex considered
Best-RMSD pose (to X-ray)out of 10 docked poses considered
22© 2007 Accelrys, Inc.
QM/MM Application: Cation-Pi Interaction ModelingQM/MM Application: Cation-Pi Interaction Modeling
• Investigate the binding of Compound 1(active against Histamine H3 receptor) on AChE1
• Goal was to design dual-acting compound• Hypothesis of two cation-pi interactions
between ligand and receptor
• Docking (CDOCKER) of Compound 1 into AChE receptor (PDB ID 1EVE) yielded a pose in position to make cation-Pi interactions
• Cation-Pi not modeled well by force fields
• QM/MM geometry optimization suggests cation-Pi interactions
– 51 hrs on 2 processors– Multiplicity: Smart– Quality: Ultra Coarse– Infinite nonbonded cutoffs– No constraints/restraints
1. Bembenek, S. D.. et al., Bioorg. Med Chem. (2008), doi:10.1016/j.bmc.2007.12.048
Einitial = -15676.278608 kcal/molEfinal = -16904.454283 kcal/mol
23© 2007 Accelrys, Inc.
QM/MM Application: Optimizing Heme systemsQM/MM Application: Optimizing Heme systems
• Starting Structure: PDB ID 1P2Y1, Cytochrome P450CAM in complex with (S)-(-)-Nicotine
1. Biochemistry 42: 11943-11950
• improved coordination between Arg and heme carboxyl groups• coordination of Fe (II)
Arg 112
Cys 357
Arg 299
His 355
nicotine
Arg 112
Cys 357
Arg 299
His 355
nicotine
QM/MM min.
2 proc. 2.6 GHz Xeon ca. 4 days
24© 2007 Accelrys, Inc.
QM/MM Application: Optimizing Heme systemsQM/MM Application: Optimizing Heme systems
• Starting Structure: PDB ID 1P2Y1, Cytochrome P450CAM in complex with (S)-(-)-Nicotine
1. Biochemistry 42: 11943-11950
Initial QUANTUMm Energy = -29288.570302 kcal/mol
Initial QM Energy = -13252.109685 kcal/mol
Initial MM Energy = -16036.460617 kcal/mol
QUANTUMm Energy = -33719.154699 kcal/mol
QM Energy = -14279.192571 kcal/mol
MM Energy = -19439.962129 kcal/mol
6-coordination of Zinc in QM/MM optimized structureNo constraints/restraints were used in the QM/MM optimization experiment
25© 2007 Accelrys, Inc.
QM/MM Application: Modeling Metals in ProteinsQM/MM Application: Modeling Metals in Proteins
From Jain et al , PROTEINS 2007
ligand bound to zinc ion
development of zinc force field difficult
Zinc Metalloproteins: important drug targets
coordination patternelectrostatics vdW interactions
QM/MM description challenging
large QM zoneQM/MM bonds
26© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Previous study1 describes design and docking studies with matrix metalloproteinase-9 (MMP-9) and a set of hydroxamate inhibitors
• The study was replicated in Discovery Studio 2.1– Sketch “Compound 1”– Dock to MMP9 receptor (PDB ID 1GKC) with CDOCKER
1. J. Med. Chem, 2005, 48, 5437-54472. J. Med. Chem. 2002, 45, 919-929
Known hydroxamate interactions in MMP-9 binding site2
Top docked pose using CDOCKER
27© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Previous study1 describes design and docking studies with matrix metalloproteinase-9 (MMP-9) and a set of hydroxamate inhibitors
• The study was replicated in Discovery Studio 2.1– Sketch “Compound 1”– Dock to MMP9 receptor (PDB ID 1GKC)– Take First Pose, optimize protein-ligand complex with QM/MM
1. J. Med. Chem, 2005, 48, 5437-54472. J. Med. Chem. 2002, 45, 919-929
28© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Some details of QM/MM experiment– 3 His, Zinc, Glu402, Ligand included in QM region– Cut between QM and MM region made at the CA-CB bond of residue
side chains– 5Å shell around QM region subjected to MM (CHARMm)– Rest of the system kept frozen (as per published study1)– 2000 steps of minimization, PBE Functional, Ultra-Coarse setting
(Basis Set: minimal, Integration Grid: xcoarse, DMol3 Cutoff 3.0 Å, SCF Density Convergence 5.0e-4)
– 7 hours on 4 CPU 1.8GHz Opteron machine
1. J. Med. Chem, 2005, 48, 5437-5447
29© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Previous study1 describes design and docking studies with matrix metalloproteinase-9 (MMP-9) and a set of hydroxamate inhibitors
• The study was replicated in Discovery Studio 2.1– Sketch “Compound 1”– Dock to MMP9 receptor (PDB ID 1GKC)– Take First Pose, optimize protein-ligand complex with QM/MM
1. J. Med. Chem, 2005, 48, 5437-54472. J. Med. Chem. 2002, 45, 919-929
Before QM/MM (Docked Pose) After QM/MM
Glu402Glu402
Zn
His411
His405
His401 Zn
His411
His405
His401
30© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Previous study1 describes design and docking studies with matrix metalloproteinase-9 (MMP-9) and a set of hydroxamate inhibitors
• The study was replicated in Discovery Studio 2.1– Sketch “Compound 1”– Dock to MMP9 receptor (PDB ID 1GKC)– Take First Pose, optimize protein-ligand complex with QM/MM
1. J. Med. Chem, 2005, 48, 5437-54472. J. Med. Chem. 2002, 45, 919-929
QM/MM optimized distances and partial charges in a hydroxamate-MMP9 complex from a published study1
Glu402
Zn
His411
His405
His401
31© 2007 Accelrys, Inc.
QM/MM Application: Optimization of MMP Binding SitesQM/MM Application: Optimization of MMP Binding Sites
• Comparison of post-optimized interactions of two MMP-9 actives– Ongoing work: QM/MM-based scoring and rank-ordering of actives in the series1,2
1. J. Med. Chem, 2005, 48, 5437-54472. J. Med. Chem. 2002, 45, 919-929
Ki = 5.05 nM Ki = 0.08 nM
QM/MM optimized distances and partial charges in a hydroxamate-MMP9 complex from a published study1
Glu402
Zn
His411
His405
His401
Glu402
Zn
His411
His405
His401
QM/MM optimized distances and partial charges in a hydroxamate-MMP9 complex from a published study1
Glu402
Zn
His411
His405
His401
Glu402
Zn
His411
His405
His401
QM/MM Inter E =-246.95 Kcal/mol
QM/MM Inter E =-266.92 Kcal/mol
“Compound 1” “Compound 20”
32© 2007 Accelrys, Inc.
Summary/ Future PlansSummary/ Future Plans
• QM/MM methods have been shown to provide improvement over pure force field (CHARMm) calculations
• QM/MM methods have been applied in real-life computational tasks– Improved partial charges for docking– Modeling of special interactions such as cation-pi– Refinement of heme-containing systems– Optimization of metalloprotein active sites
• accurate interaction energies• Ongoing validation
– QM/MM-based scoring function– Comparison of DMol3 ESP charges with AM1-BCC, others– Torsion profiles (ΔE vs. torsional angle) for select small molecules
• Future developments on QM/MM will be exclusively based on customer feedback– QM/MM based scoring function– Semi-empirical methods for QM– Modeling reaction mechanisms
33© 2007 Accelrys, Inc.
Thank you!!!Thank you!!!
• Thank You for attending today’s webinar. If you have any further questions please e-mail me at: [email protected]
• You can also contact us using the form on our website: http://accelrys.com/company/contact/
• We will be exhibiting at the following upcoming events:– CHI Protein Kinase Targets (June 23 – 25, Boston, Booth #4)– CHI Structure Based Design (June 25 – 27, Boston, Booth #7)– Drug Discovery Technology and Development (August 4 – 7, Boston, Booth #512)– ACS Fall 2008 (August 17 – 21, Philadelphia, Booth #211)
• Reminder: the next webinar in this series will be:
– Pharmacophore Guided Fragment-Based Drug Design Dr. Tien Luu – July 10, 2008 at 7am PST and 10am PST
34© 2007 Accelrys, Inc.
QM ↔ MM coupling: Short-rangeQM ↔ MM coupling: Short-range
•QM ↔ MM van-der-Waals interactions handled classically (i.e., by MM server)
•Requires Lennard-Jones parameters for QM region
35© 2007 Accelrys, Inc.
HOMO/LUMO Visualization (Work in Progress…)HOMO/LUMO Visualization (Work in Progress…)
Diels-Alder Reaction
The electron-rich HOMO of the diene and the Electron-vacant LUMO of the dienophile mustbe in a stacked orientation (top-bottom) formaximal overlap of the orbitals for the reactionto proceed
Diene Dienophile
HOMO LUMO