Sandwich and T-shaped configurations of substituted benzene dimers were studied by second-order perturbation theory to determine how substituents tune pi-pi interactions. Remarkably, multiple substituents have an additive effect on the binding energy of sandwich dimers, except in some cases when substituents are aligned on top of each other. The energetics of substituted T-shaped configurations are more complex, but nevertheless a simple model that accounts for electrostatic and dispersion interactions (and direct contacts between substituents on one ring and hydrogen atoms on the other), provides a good match to the quantum mechanical results. These results provide insight into the manner by which substituents csan be utilized in supramolecular design.

Noncovalent C-H/pi interactions are prevalent in biochemistry and are important in molecular recognition. In this work, we present potential energy curves for methane-benzene, methane-phenol, and methane-indole complexes as prototypes for interactions between C-H bonds and the aromatic components of phenylalanine, tyrosine, and tryptophan. Second-order perturbation theory (MP2) is used in conjunction with the aug-cc-pVDZ and aug-cc-pVTZ basis sets to determine the counterpoise-corrected interaction energy for selected complex configurations. Using corrections for higher-order electron correlation determined with coupled-cluster theory through perturbative triples [CCSD(T)] in the aug-cc-pVDZ basis set, we estimate, through an additive approximation, results at the very accurate CCSD(T)/aug-cc-pVTZ level of theory. Symmetry-adapted perturbation theory (SAPT) is employed to determine the physically significant components of the total interaction energy for each complex.

S/p interactions are prevalent in biochemistry and play an important role in protein folding and stabilization. Geometries of cysteine/aromatic interactions found in crystal structures from the Brookhaven Protein Data Bank (PDB) are analyzed and compared with the equilibrium configurations predicted by high-level quantum mechanical results for the H 2 S-benzene complex. A correlation is observed between the energetically favorable configurations on the quantum mechanical potential energy surface of the H 2 S-benzene model and the cysteine/aromatic configurations most frequently found in crystal structures of the PDB. In contrast to some previous PDB analyses, configurations with the sulfur over the aromatic ring are found to be the most important. Our results suggest that accurate quantum computations on models of noncovalent interactions may be helpful in understanding the structures of proteins and other complex systems.Keywords: molecular recognition; protein structure; computational analysis of protein structure; forces and stabilityThe tertiary structure of proteins is determined by a variety of intermolecular interactions. Traditional hydrogen bonding is one critical noncovalent interaction that can play a large role in determining structure, but many other, weaker, noncovalent interactions can also contribute. Understanding the underlying nature, strength, and directionality of these interactions is important for the prediction of the optimal structure of proteins and the dynamics of their folding. Unfortunately, isolating an individual interaction in a complex protein structure, and separating the effect of this interaction from that of other weak interactions and solvent effects, would be nearly impossible. Computational techniques offer a way to systematically and rigorously characterize the strength of various types of interactions by providing highly accurate potential energy curves for small model systems. For example, converged ab initio computations have deepened our understanding of p-p interactions through studies of the simplest possible prototype system, the benzene dimer (Hobza et al. 1994(Hobza et al. , 1996Tsuzuki et al. 1994Tsuzuki et al. , 2000Tsuzuki et al. , 2002Jaffe and Smith 1996;Tsuzuki and Lüthi 2001;Sinnokrot et al. 2002;Sinnokrot and Sherrill 2006).Such an approach assumes that the model system accurately captures the essential physics of the nonbonded interaction as it would occur in larger systems. This study aims to address the validity of this assumption by providing highly accurate potential curves for several model configurations of the H 2 S-benzene complex (see Fig. 1) and comparing these results with the preferred geometries of cysteine/aromatic contacts observed in the Brookhaven Protein Data Bank (PDB).Reprint requests to: C. David Sherrill, School of Chemistry and Biochemistry, 901 Atlantic Drive, Atlanta, GA 30332-0400, USA; e-mail: sherrill@gatech.edu; fax: (404) 894-7452.Article published online ahead of print. Article and publication date are at http://www...

Noncovalent interactions between pi systems are central to understanding protein folding and the stability of DNA. Considerable controversy exists about whether substituent effects in pi-pi interactions can be understood purely on the basis of electrostatic interactions or whether other effects must be included to understand observed trends. In this work, we show that in general, pi-pi interactions are not governed solely by electrostatic control. We do not observe a linear correlation between the relative interaction energies and the sums of Hammett parameters in the case of multiply substituted face-to-face benzene dimers. Instead, differential dispersion effects can be so large that even molecules with wildly different electrostatic potentials can exhibit similar attractions to benzene.

We provide a first-principles methodology to obtain converged results for the lattice energy of crystals of small, neutral organic molecules. In particular, we determine the lattice energy of crystalline benzene using an additive system based on the individual interaction energies of benzene dimers. Enthalpy corrections are estimated so that the lattice energy can be directly compared to the experimentally determined sublimation energy. Our best estimate of the sublimation energy is 49.4 kJ mol(-1), just over the typical experimentally reported values of 43-47 kJ mol(-1). Our results underscore the necessity of using highly correlated electronic structure methods to determine thermodynamic properties within chemical accuracy. The first coordination sphere contributes about 90 % of the total lattice energy, and the second coordination sphere contributes the remaining 10 %. Three-body interactions are determined to be negligible.