Modeling the complexation of substituted

Proc. Natd. Acad. Sci. USA

Vol. 90, pp. 1194-1200, February 1993

Colloquium Paper

This paper was presented at a colloquium entitled "Molecular Recognition, " organized by Ronald Breslow, held

September 10 and 11, 1992, at the National Academy of Sciences, Washington, DC.

Modeling the complexation of substituted benzenes by a cyclophane

host in water

(molecular recognition/binding affinities/Monte Carlo simulations)

WILLIAM L. JORGENSEN* AND TOAN B. NGUYEN

Department of Chemistry, Yale University, New Haven, CT 06511-8118

ABSTRACT Monte Carlo statistical mechanics simula￾tions have been used to study the complexation of disubstituted

benzenes by Diederich's octamethoxy tetraoxaparacyclophane

host. Relative free energies of binding were obtained in water

at 250C for benzene, p-xylene, p-cresol, p-dicyanobenzene, and

hydroquinone from statistical perturbation theory. The com￾puted results agree well with experimental data, including the

binding affinity of benzene, which was determined after the

calculations were completed. The computed structures for the

complexes reveal details that are important for understanding

the order of binding affinities. It is found that hydroquinone

protrudes from one side of the complex and participates in

hydrogen bonds between one hydroxyl group and two water

molecules and in an intracomplex hydrogen bond between the

other hydroxyl group and ether oxygens. The calculations also

show a clear preference for binding p-cresol with the hydroxyl

group hydrated rather than inside the host's cavity.

The central role of intermolecular binding events in biochem￾istry and the potential for developing synthetic catalysts and

novel materials have helped foster great experimental (1-5)

and computational (6-19) interest in host-guest chemistry.

The interplay between theory and experiment has been aided

by the development of methodology that allows computation

of relative and absolute free energies of binding (6, 15, 16) and

by the ability of fluid simulations to provide exquisite struc￾tural details. Much computational effort has been directed at

enzyme-ligand binding and the complexation of atomic ions

by organic hosts (6-14), though complexes of neutral guests

with organic hosts are now receiving increased attention

(17-19). Water-soluble hosts that bind neutral guests are of

particular interest as models of biological systems and as

starting points for the design of nonenzymatic catalysts.

Important contributions have been made in this area by many

researchers, as reviewed by Diederich (4). The most common

examples feature cyclodextrins and cyclophanes, which have

relatively hydrophobic binding cylinders or slots. We have

chosen to direct computational efforts at the cyclophanes in

view of their potential structural diversity and the availability

of experimental binding data for many systems. They also

provide a rich venue for investigating the factors that control

binding in water and the opportunity to complement the

experimental studies by helping characterize the structures of

the complexes, including specific interactions between host,

guest, and water.

Our first effort has been aimed at Diederich's octamethoxy

tetraoxaparacyclophane, 1,

OCH3 OCH3

H3C /N OCH3,_ICH H3 CH30 7 CH3

(CH2)n

OCH3 OCH3

1 (n = 3) 2 (n = 4)

which binds substituted benzenes in its slot-like cavity (20-

22). The observed binding results for 1 and 2 reflect a complex

mixture of hydrophobic association, electron donor￾acceptor interactions, and specific substituent hydration ef￾fects (21, 22). Consequently, the initial computational goals

have been to assess the ability of Monte Carlo statistical

mechanics simulations in handling these effects, to reproduce

known relative free energies of binding and predict unknown

ones, and to clarify fundamental structural questions con￾cerning the positioning of the guests in the host's cavity and

the hydration of substituents, which bear on the origin of the

binding differences. The guests that were chosen for study

are p-xylene, benzene, p-cresol, p-dicyanobenzene, and hy￾droquinone. The results for benzene and p-cresol were not

known at the outset of the work and provided a basis for a

joint theoretical and experimental study (19). A complete

report on the computations is now given.

Computational Procedure

The calculations were performed with version 3.1 of the BOSS

program, which permits sampling for any designated bonds,

bond angles, and dihedral angles in the solutes (23). The

stretching and bending force constants have been adopted

from the AMBER force field (24), while the nonbonded inter￾actions are described by the OPLS potential functions (25, 26).

The potential energy between two molecules, AEab, consists

of Coulomb and Lennard-Jones interactions between the

atoms i on a and the atoms j on b, which are separated by a

distance rV, (Eq. 1). Geometric combining rules are used for

the Lennard-Jones parameters, e and a (Eqs. 2).

AEab = >a {qiqje2/r, + 4Eu( rj/ri)12 )6]- [11

ij

E (C i j)12 a. = (,)1.2r [2]

Intramolecular nonbonded interactions are also treated by

Eq. 1 for atoms separated by more than three bonds. The

torsional energy, V(O), is given by a Fourier series for each

dihedral angle 4 with coefficients obtained by fitting exper￾imental data or reliable gas-phase calculations (Eq. 3).

*To whom reprint requests should be addressed.

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