1. Introduction & Objective :
References:
From Achiral to Chircal Molecular Bis-Porphyrin Ladders
Karolina Parciak1, Ashley Delpeche1, Gloria Proni2, Ana G. Petrovic1
1 Department of Life Sciences, New York Institute of Technology, New York, NY, USA.
2 John Jay College of Criminal Justice, Science Department, New York, NY, USA.
• The double-strand helical structures are frequently found in nature and are closely related to the physiological
functions of biomolecules, such as nucleic acids (DNA, RNA, even PNA) and proteins.
• Although helical-induction of single-strand helices has been performed in the past, for example, by covalently
adhering enantiopure chiral additives to foldable polymers1,2, the induction of double-strand helices is rare.
• The Objective of the present research is to develop a novel,
sensitive tool for helical-sense programming
of double-stranded biomolecular architectures.
• The ability to induce supramolecular chirality and control the screw-sense and the degree of helicity plays a vital
role in the frontier of biomolecular recognition, material science and possibly information storage.
• The potential utilities of being able to reversibly transition from a ladder to a right- or left-handed helical-duplex
are:
a) in the field of binary bio-information storage (0,1), where a ladder could represent a molecular analogue of a
state “0” and helix could represent a molecular analogue of state “1”.
b) in development of a molecular gauge for double-stranded helix stability in biomolecular systems.
Specific Methodology :
Theoretical
Molecular
Mechanics
Methods
1. Building the ladders (6mer, 8mer, 10mer, 12mer, etc.), analogous ladders with porphyrins
and seeding the guest at various orientations;
2. Initial Minimization of host-guest ladders via Molecular Mechanics based, OPLS-2005
force-field, implicit H2O solvent model included;
3. Application of three Monte Carlo, Molecular Mechanics algorithms, OPLS-2005 force-
field;
4. Resorting to Single Point Energy calculation via Quantum Mechanics, DFT, 6-31G(TM)
basis set;
5. Determination of Bolzamann population for identified conformations (minimized
geometries).
Note: Molecular Modeling based simulations are accomplished via Schrodinger/Macro Model software,
while the Quantum Mechanical energy refinement will be accomplished via Schrodinger/Jaguar
software.
Monte Carlo Method: survey of potential energy surface via
random conformational changes in all bond exhibiting rotational
degrees of freedom.
• Two Zn-porphyrins are covalently attached to the scaffold of an achiral ladder-duplex.
• A small chiral guest is added in order to form a host/guest complex with the bis-porphyrins.
• The coordination between the nucleophilic groups of the chiral guest and Zn-centers of porphyris should induce a
helical-twist (stereo-differentiation) between the porphyrins, as similarly seen in the porphyrin-tweezer methodology3.
• As a result of stereo-differentiation, the two porphyrins should adopt a preferred chiral twist.
• The sign and the twist-sense should be governed by the Absolute Configuration of the chiral guest, while the extent
of stereo-differentiation (degree of twisting) via variation of the steric size of the guest (methyl vs. benzyl moieties).
General Methodology :
Zn+
Zn-porphyrin
handle
Zn Zn
+
NH2 or OH NH2 or OH
chiral guest
Zn Zn
ZnZnZnZn
achiral ladder
achiral conjugate
(host)
helical-sense induction
and chirality propagation
guest
coordination
NH2 or OH NH2 or OH
a) b) c) d)
Monte Carlo
(MC)
Algorithms
Monte Carlo Multiple Minimum (MCMM):
torsional sampling which generates trial conformations by
randomly adjusting rotatable bonds.
Systematic Torsional Sampling (SPMC): method
employs a systematic search instead of a random search.
The search begins at low torsional resolution (120º), searches all
angles without duplicating coverage, then doubles the resolution.
Mixed Torsional/ Low mode sampling (MTLMS):
combination of the random torsional changes with the low-mode
steps (explores the low-frequency eigenvectors of the system,
which are expected to follow “soft” degrees of freedom).
GibbsFreeEnergy
RTEEi
i
i
e
N
N
P /)(
0
0
  
i
iP 1
Boltzmann Relation:
Summary & Future Outlook :
1. Yashima, E.; Katsuhiro, M. Macromolecules (Review). 2008, 41, 3–12.
2. Sanji, T.; Takase, K.; Sakuria, H. J. Am. Chem. Soc. 2001, 123, 12690–12691.
3. Berova, N.; Pescitelli, G.; Petrovic, A. G.; Proni, G. Chemical Communications. 2009,
5958-5980.
Ladder Candidates:
Synthetic Candidates for Ladder :
NH2
H2C
C
O
OH
NH2
CH2
CO
NH
CH2
CO
NH
CH2
CO
NH
CH2
CO
OH
N N
HOOC COOH H2C
HN
C O
H2C
HN
C O
H2C
HN
C O
H2C
H2N
C
HO
O
X =
4 units
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
X = 6, 8, 10, 12, 16, 20
monomeric units
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a) b)
OO
OO
OO
Ladder examples:
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
X = 6-20
monomeric units
Me
O
O NH
HN
NH2
Me
O
O
HO
OH
H2N NH2
HN
Me
O
O OH
O
O NH
HN
NH2
HN O
O OH
Me
Me
N N
+
• The methyl-based guest presents a smaller steric demand then the benzyl-based analogue, as evidenced by the extent of
inducted helical pitch;
• In order to impart a uniform double-stranded helical chirality, we came to understanding that the ladder has to exhibit a
dynamic balance of two factors:
a) sufficient flexibility for chirality to propagate from down the backbone of the ladder,
b) sufficient hydrogen bond reinforcement that keeps the two ladders from collapsing into a random-coil conformations;
• Right-handed helical induction has been observed for some of the investigated 6mers.
• We will continue to explore the most optimal length for helical chiral-induction;
• All molecular modeling geometries await single point energy evaluation based on QM to determine relative stability
between helical and random (collapsed) conformations;
further
subjected to
the MC search
Theoretical Methods and Data:
The preliminary Molecular Modeling Minimizations, carried-out till convergence
(no lower energy conformation obtained upon iterative minimization) provide insight
into propensity towards helical induction for the following two ladder-architectures:
&
NYIT travel grant
provided by Dean Yu
Acknowledgements:
Synthetic Scheme of First Ladder :
Chiral Guests
larger
benzyl-based guest
N
N
H
NH2
H O
smaller
methyl-based guest
N
N
H
NH2
H O
NH2
H2C
C
O
OH
NH2
CH2
CO
NH
CH2
CO
NH
CH2
CO
NH
CH2
CO
OH
N N
HOOC COOH H2C
HN
C O
H2C
HN
C O
H2C
HN
C O
H2C
H2N
C
HO
O
X =
4 units
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
X = 6, 8, 10, 12, 16, 20
monomeric units
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a) b)
OO
OO
OO
Ladder examples:
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
X = 6-20
monomeric units
Me
O
O NH
HN
NH2
Me
O
O
HO
OH
H2N NH2
HN
Me
O
O OH
O
O NH
HN
NH2
HN O
O OH
Me
Me
N N
+
n = 3
monomeric unit
of ladder scaffold
The selected Four Ladder Candidates:
monomeric unit
of ladder scaffold
H-bonding
bridging unit
+
NH2
H2C
C
O
OH
NH2
CH2
CO
NH
CH2
CO
NH
CH2
CO
NH
CH2
CO
OH
N N
HOOC COOH H2C
HN
C O
H2C
HN
C O
H2C
HN
C O
H2C
H2N
C
HO
O
X =
4 units
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
X = 6, 8, 10, 12, 16, 20
monomeric units
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a) b)
OO
OO
OO
Ladder examples:
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
X = 6-20
monomeric units
Me
O
O NH
HN
NH2
Me
O
O
HO
OH
H2N NH2
HN
Me
O
O OH
O
O NH
HN
NH2
HN O
O OH
Me
Me
N N
+
NH2
H2C
C
O
OH
NH2
CH2
CO
NH
CH2
CO
NH
CH2
CO
NH
CH2
CO
OH
N N
HOOC COOH H2C
HN
C O
H2C
HN
C O
H2C
HN
C O
H2C
H2N
C
HO
O
X =
4 units
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
X = 6, 8, 10, 12, 16, 20
monomeric units
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a) b)
OO
OO
OO
Ladder examples:
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
X = 6-20
monomeric units
Me
O
O NH
HN
NH2
Me
O
O
HO
OH
H2N NH2
HN
Me
O
O OH
O
O NH
HN
NH2
HN O
O OH
Me
Me
N N
+
n = 3n = 2
n = 2
Seeded Host-Guest Complexes:
MCMM Monte Carlo Search  resulted representative architectures, some of which are helical
benzyl-based guestmethyl-based guest
NH2
H2C
C
O
OH
NH2
CH2
CO
NH
CH2
CO
NH
CH2
CO
NH
CH2
CO
OH
N N
HOOC COOH H2C
HN
C O
H2C
HN
C O
H2C
HN
C O
H2C
H2N
C
HO
O
X =
4 units
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
X = 6, 8, 10, 12, 16, 20
monomeric units
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a) b)
OO
OO
OO
Ladder examples:
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
X = 6-20
monomeric units
Me
O
O NH
HN
NH2
Me
O
O
HO
OH
H2N NH2
HN
Me
O
O OH
O
O NH
HN
NH2
HN
O
Me
N N
+
n = 2
Methyl-guest & L1
minimization no solvent
E= -4923.90kJ
Initial helical stride
D = - 6.7 deg
Methyl-guest & L1
minimization no solvent
E= -4861.409 kJ
Irregular helix
D = + 17.7 deg
Methyl-guest & L1
minimization no solvent
E= -4872.771 kJ
Irregular conformation
D = + 45.7 deg
Benzyl-guest & L1
minimization no solvent
E= -4877.032 kJ
Irregular helix
D = + 12.8 deg
Benzyl-guest & L1
minimization no solvent
E= -4788.264 kJ
Irregular conformation
D = + 12.7 deg
Benzyl-guest & L1
minimization no solvent
E= -5226.174kJ
Irregular conformation
D = + 10.6 deg
NH2
H2C
C
O
OH
N N
HOOC COOH
n
H2C
C
O
OH
n
NH2
NH2
H2C
C
O
OH
n
Monomeric Units:
Bridging Units: *
n = 1-3
OO
O
OHO
OH
O
OHO
OH
H2
C
1-2
a)
OO
HO OH
HO
OO
OH
N N
R
R =H, Me, t-Bu
Me
O
O
HO
OH
H2N NH2
N N
+
n = 2
L1
L1B
L2
L2B