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LYSASPGLYPROCYSASNTRPGLYALAVALGLN
GLUALALEUGLYCYSARGLYSSERASNGLUTYR
Subsystem k Subsystem k+4
Divide and Conquer
“Onion-Skin” Strategy
χ ∈ χ ∈
µ ν
α α
α
P
µ ν
= ∑
µ ν
µ ν µ ν = χ µ ∈ χ ν ∈
α =
µν
α
α α α α =
µ ν = ∑ ( µ ) ν
+
α
ε − ε )
[( ]
α α α
∑ µµ = ∑ ∑ µµ ∑ µ
=
µ = µ = α =
Divide & Conquer ("DivCon") vs Standard Calculation
Linear vs. Exponential Scaling
(Seconds required to complete one SCF Cycle)
3000
CPU Resources Required
2500
1000
500
"Divide & Conquer"
Scales Linearly
0
0 100 200 300 400 500 600
Number of Atoms Per Molecule Drug targets
Small molecule
Large Biomolecules
drug candidates
(Proteins ~2,500 atoms)
(50-150 atoms)
Errors in Heat of Formation Using D&C
Implicit Solvation in
Biological Systems
• Use PoissonBoltzmann Theory in conjunction with
Divide and Conquer.
• CM1/CM2 charges were key to making this approach
sucessful.
• Model fit (nonpolar term) to simultaneously
reproduce solvation free energies of small molecules
and LogP values of a wide range of compounds.
PB: Tannor, Marten, Murphy, Friesner, Sitkoff, Nicholls, Honig, Rignalda, Goddard
J. Am. Chem. Soc. 1994, 116(26), 1187511882.
CM1 and CM2: Li, Zhu, Cramer, Truhlar J. Phys. Chem. 1998, 102, 18201831.
Storer, Giesen, Cramer, Truhlar J. ComputerAided Molecular Design 1995, 9, 87110.
Implicit Solvation in Biological
Systems - Proteins
Solvation Free Energies of Proteins in Water Calculated by DivConPB Methodology.
Gogonea and Merz J. Phys. Chem. A. 1999, 103, 51715188
Do We Understand
Intermolecular Interactions
between Biomolecules?
Current understanding is at the
classical level, but
Intermolecular (and intramolecular
in biomolecules) interactions are
inherently quantum in nature.
Can we use quantum chemistry to
better understand interactions in
biomolecular systems?
Glutamic Acid N
O Variations in
Min Max
Point Charges
O (Ð) O (0.716, 0.413)
• Variation of on polar atoms is
(0.135, +0.140)
Histidine N
N +/0.3e (Mulliken, CM1 or CM2)
N
Glycine N
O (0.543, 0.292)
• Arises due to variations in the
local environment of the atoms
O
Asparagine N
(0.574, 0.332) O
O (0.566, 0.337)
Aspartic Acid N
O
(Ð)
O
O (0.569, 0.342)
Alanine N
Charge Transfer Effects : HIV-1 Protease
0.1
0.05
-0.15
-0.2
-0.25
Inhibitor
+ve ∆q => Charge transferred from -ve ∆q => Charge transferred from
Inhibitor to Protease Protease to Inhibitor
How well do We Understand
Biomolecular Intermolecular
Interactions?
Current understanding has
limitations due to the neglect of
polarization and charge transfer
effects.
P L P L
L
P
Methodology: Thermodynamic Cycle to Calculate
Free Energy of Binding
P PS
S Gas
Phase
+
Solvent
+
60% 56%
53% 52% 51%
50% 47%
44% 44% 43%
40%
2
30%
R
25%
23%
10% 8%
0%
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M
Score Function
Q
(a) parameterized on this data set; (b) parameterized on other data sets
Source: Renxiao Wang, Yipin Lu and Shaomeng Wang, Comparative Evaluation of 11 Scoring Functions for Molecular Docking J.Med.Chem. 2003, 46, 2287-2303. For QMScore date, Kaushik
Raha, Merz lab at Pennsylvania State University, unpublished study.
HIV-1 Protease - XK263 (1hvr)
-1000
0 5 10 15 20
-1200
-1400
-1600
-1800
TotalScore
-2000
-2200
2
Rank, RMSD
Xscore
TotalScore DrugScore Autodock
Cerius2/PLP Cerius2/LUDI Cerius2/PMF
SYBYL/F-Score SYBYL/Gscore
SYBYL/D-Score
Cerius2/LigScore
Score Function SYBYL/ChemScore
-400
-600
TotalScore
-800
-1000
-1200
RMSD (Ao)
12
10
Rank,4 RMSD
Xscore
DrugScore Autodock
TotalScore
Cerius2/PLP Cerius2/LUDI Cerius2/PMF
SYBYL/F-Score SYBYL/Gscore
SYBYL/D-Score
Cerius2/LigScore
Score Function SYBYL/ChemScore
Native Rank Best Rank RMSD
Conclusions and Future Directions
• First generation (AM1 based) results are very
promising and can be readily refined.
• Explore further parameterization to improve predictive
capability.
• QM geometry optimization (ligand only) to further
refine structures.
Preliminary Studies of Semiempirical
Electron Densities of Biomolecules and
Potential Applications
Can we compute reasonable electron densities (EDs) of
biomolecules using semiempirical Hamiltonians?
How good are they with respect to experimental EDs? Ab
initio computed EDs?
What are their potential uses in Xray studies of
macromolecules?
Experimental X-Ray Crystallography
Xray experiments measure the intensities I(h k l) of the diffraction
peaks and derive the structure factors F(h k l).
2
I(h k l) = F(h k l)
Fourier transformation is used to obtain the electron density
distributions ρ(x y z) in molecule crystals.
1
ρ(x y z) = ååå F(h k l) exp [- 2pi(hx + ky + lz) + ia (h k l)]
V h k l
Because of the lack of phase angles α(h k l), special techniques have
to be applied (heavyatom methods, anomalous scattering, and
molecular replacement, etc.) and structure determination involves an
iterative process called refinement.
A Typical Diffraction Spectrum from an
XRD Experiment
Reflections
only appear at
discrete
angles (h k l).
Peak
intensities are
related to
structure
factors by: 2
I(h k l) µ F(h k l)
Theoretical Studies of Electron Density
Distributions
Ab initio or semiempirical calculation of electron density.
2
ρ(r) = ò Y(r , r ,K ,r ,s , s ,K , s )
1 2 n 1 2 n dr2 L drn ds1 L dsn
= å å P f ( r )f (r )
mn m v
m n
Theoretical structure factors can be simulated by Fourier transformation
of theoretical densities. Methods have been described to handle/model
temperature factors.
Periodic HartreeFock and density functional calculations of small
molecules now feasible with, for example, the program CRYSTAL.
With our linearscaling technologies we can evaluate the ED of
macromolecules.
CRYSTAL: de Vries, Feil and Tsirelson Acta. Cryst. 1999, B56, 118123
QMED Calculations of Macromolecules
with Semiempirical Hamiltonians
Typical semiempirical models employ the core
approximation, but we need the core electron density
in order to match with experiment.
Full EDs can be obtained by augmenting the QM
derived valence EDs with spherical core EDs.
The main question remains, though How good are
these EDs?
AM1 EDs: Ho, Schmider, Edgecombe and Smith, Jr. Int. J. Quantum Chem.1994, S28, 215
Core model: Cioslowski and Piskorz Chem. Phys. Lett. 1996, 255, 315319
Quantum Mechanical Electron
Densities of p-Nitropyridine-N-Oxide
AM1 (DIVCON) HF/631G* (G98)
Quantum Mechanical Electron
Densities of a Protein Crambin
Ultrahigh resolution structure (0.54Å,
Teeter et al., 2000).
46 residues, 648 atoms.
The QM ED map currently contains only
the electron distribution for a static structure
as opposed to a time and space average, but
otherwise agrees well with the experimental
map.
A Small Molecule Test Case
Recent work by Perpetuo et al (Acta Cryst.
B55, 7077, 1999).
3 molecules studied: N(trifluomethyl)
formamide, N(2,2,2trifluoethyl) formamide,
and 2,2,2trifluoethyl isocyanide.
1170 independent reflections.
70 parameters used in refinement.
R=0.0498
Preliminary Results
50
45
y = 0.6991x
R 2 = 0.8753
40
35
30
25
20
15
10
0
0 10 20 30 40 50 60 70
Preliminary Results -- Cont’d
Structure Factors (Atomic v.s. Raw) Structure Factors (QM v.s. Raw)
70 45
40
60
35 y = 0.5594x
y = 0.8213x R 2 = 0.9221
50 2
R = 0.9291
30
40
25
20
30
15
20
10
10
5
0 0
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
R=0.196 R=0.173
Current Status and Future Directions
Currently further validating computed ED on small molecules.
Application areas we are pursuing by providing aspherical ED
descriptions:
Aid the macromolecular refinement process by introducing
another constraint.
Allow for deconvolution of anisotropic density
distributions from the anisotropic temperature factors.
Study macromolecules with the Atoms in Molecules (AIM)
theory.
Summary
Our Vision of Quantum
Biology
Exploit
Linear-scaling algorithms
Parallel computing
Model chemistries
Semiempirical Hamiltonians
Density Functional Theory
Hartree-Fock Theory
Quantum Monte-Carlo
Exploit ensemble generation protocols
Use classical models to generate ensembles
Novel sampling approaches
Spectroscopy
NMR
X-ray
Exploit statistical approaches
Leverage the repetitive nature of biology
Bioinformatics databases
General Conclusions
• Application of QM to large biomolecular
systems are opening up new avenues to aid in
our understanding of biomolecular solvation,
inhibition, etc.
• QM gives a better account of electrostatic
interactions than typical classical models.
• Quantum mechanics and classical mechanics
can work synergistically to achieve our desired
goal of understanding biomolecular structure,
function and inhibition.
Acknowledgements
• Steve Dixon
• Arjan van der Vaart
• Dimas Suarez
• Lance Westerhoff
• Martin Peters
• Kaushik Raha
• Ed Brothers
• Andrew Wollacott
• Ken Ayers
• Bryan Op’t Holt
• Ning Liao
• Xiadong Zhang
• Bing Wang
• Guille Estiu
Acknowledgements
• DOE
• NIH
• NSF
• AMBER Development Team
• Pharmacopeia, Inc.
• QuantumBio Inc.