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...