Quantum Chemistry in Drug

Design and Discovery: Where

We are and Where We are Going
 Motivation
 Linear-Scaling QM
 QM based protein/small molecule scoring
function
 Spectroscopy

NMR
 Electron Density and X-Ray
 Status of Theoretical
Approaches/Problems in
Biology
Fundamental problems remain unsolved
 Water
 Hydrophobic effect
 Protein folding
 Protein/small molecule interactions (drug design)
 etc.

Hence, current theoretical approaches are insufficient

Current Theoretical Approaches
to Problems in Biology
Classical Mechanics (standard approach)
 Molecular mechanical potentials

Purely empirical potentials

QSAR analysis
Statistical Mechanics (standard approach)

Analyze trajectories (g(r), correlation functions, etc.)
 Free energy methods
Mathematical tools (standard for all potentials)
 Energy minimization

Molecular dynamics
 etc.
Quantum Mechanics (less common approach)
 Cluster models (continuum solvation)
 QM/MM

Linear-scaling QM
Strengths and Weaknesses of
Classical and Quantum
Potentials
Classical Mechanics (standard approach)
 Highly approximate models (Coulombic electrostatics)

Rapidly evaluated

Good approach for ensemble generation
 Quality of potentials highly dependent on parameterization

Quantum Mechanics (less common approach)

 Fewer approximations (in the limit very accurate models)
 Expensive calculations

Good for examining single snapshots
 Quality of potentials are well understood
 Used to build classical models

Highly successful in organic and inorganic chemistry

Hence, applying a QM approach to biological problems is the logical next step

What are the Hurdles to a QM
Model in (Structural) Biology?
Very computationally expensive
 Linear-scaling algorithms
 Parallel computing
What model to use

Exploit model chemistries
Semiempirical Hamiltonians
Density Functional Theory
Hartree-Fock Theory
Quantum Monte-Carlo
Ensemble generation
 Novel sampling approaches
 Use classical models to generate ensembles
Spectroscopy

NMR

X-ray

etc.
Computational biology approach
 Leverage the repetitive nature of biology
 Bioinformatics databases
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
Novel sampling approaches
Use classical models to generate ensembles

Spectroscopy
NMR
X-ray

Exploit statistical approaches
Leverage the repetitive nature of biology
Bioinformatics databases
 Why Can We Think About
Using Quantum Mechanics?
 Divide and Conquer
 Divides QM system into a set of
smaller subsystems.
 “Solves” matrix diagonalization
problem.
 Parallelizable.
 Uses standard energy expressions.
 Obtain gradients using standard
methods.
S. L.Dixon and K. M. Merz, Jr. J. Chem. Phys. 104, 6643­6649 (1996)
S. L. Dixon and K. M. Merz, Jr.  J. Chem. Phys. 107, 879­893 (1997)
A. van der Vaart, D. Suarez, K. M. Merz, Jr. J. Chem. Phys. 113, 10512­10523 (2000)
 Divide and Conquer
“Onion-Skin” Strategy
Buffer Buffer
Region 1 Region 2
Core
Region

­­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

2000 Current Standard

Scales Exponentially, Rendering
It Unsuitable for Routinely Analyzing
Large Biomolecules
1500

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.

Protein  Atoms/Res/q   GRF  Greorg  Gnp    Gsol  SCRF    

         iterats
Crambin 642/46/0 ­316.7   
23.4 19.7 ­273.5 11

BPTI 888/58/+6 ­1336.3  69.7 26.6 ­1239.8 14

CspA 1010/69/0 ­1175.5  109.3 28.6 ­1073.5 15

Lysozyme 1960/129/+8 ­1936.3  129.3 45.3 ­1761.7 13

Subtilisin E   3854/275/­2 ­1856.3  166.8 74.8 ­1614.7 15

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

HIVP HIVP HIVP HIVP Ace- HIVP HIVP HIVP

A76889 A76982 A78791 Pep Indinavir SB203386 XK263
-0.05



 
-0.1
∆

-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.

Thus, QM models can significantly

contribute to increasing our
understanding of these effects
 QM Based Protein/Ligand
Scoring Function
A quantum mechanics based approach for more fundamental
understanding of ligand/drug-protein interaction.
Score function includes CT and polarization effects which are
generally ignored by standard score functions.
Score function can be systematically improved via appropriate
parameterization.
Pose generation via empirical or classical approaches.
Primary screen via empirical or classical approaches.
QM based scoring for final selection of compounds - i.e.,
secondary computational screen.

• Medicinal Chemistry Feedback:

Validate Validate and Validate some more
Protein-Ligand Binding
(Docking)
I. The Unbound State II. Ligand Recognition

P L P L

III. The Protein Ligand Complex

L
P
Methodology: Thermodynamic Cycle to Calculate
Free Energy of Binding
P PS
S Gas
Phase
+

Solvent
+

Binding Free Energy calculated as:

∆Gbs = DGbg + DGsolv
PS P
- DGsolv S
- DGsolv
DGbg = DHbg - TDSbg
DHb = DH f + ( 1 6 )LJ
g g
R
DSg = DSAC ,N,O,S + num(rot _ bonds)
 40 Protein-ligand Complexes

60% 56%
53% 52% 51%
50% 47%
44% 44% 43%

40%
2

30%
R

25%
23%

20% 17% 17%

14%

10% 8%

0%
)

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/P
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sc

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et

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Sc

Xs

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s2

to
s2
G
am
M

F-
ig
em

s2
M

Au
D

riu
ru

L/
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riu
/L

L/
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riu
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ar

Ch
D

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Ce
s2

BY
Ce
BY
np

Ce
L/

SY

riu

SY
SY
(u

BY

Ce
e

SY
or
Sc
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

-2400 RMSD (Ao)

5

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

Native Rank Best Rank RMSD

FKBP - Rapamycin (1fkb)
0
0 5 10 15 20
-200

-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

Structure Factors (QM w/o T fac v.s. Raw)

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.