On the Structure and Geometry of Biomolecular Binding Motifs (Hydrogen-Bonding, Stacking, X-H ··· π): WFT and DFT Calculations Kevin E. Riley,* ,† Michal Piton ˇa ´k, ‡,§ Jir ˇı ´C ˇ erny ´, | and Pavel Hobza* ,‡,⊥ Department of Chemistry, UniVersity of Puerto Rico, P.O. Box 23346, Rio Piedras, Puerto Rico 00931, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and Center of Biomolecules and Complex Molecular Systems, FlemingoVo nam. 2, 166 10 Prague 6, Czech Republic, Department of Physical and Theoretical Chemistry, Faculty of Natural Sciences, Comenius UniVersity, Mlynska Dolina CH-1, 842 15 BratislaVa, SloVak Republic, Institute of Biotechnology, Academy of Sciences of the Czech Republic, 142 00 Prague 4, Czech Republic, and Department of Physical Chemistry, Palacky ´ UniVersity, Olomouc, 771 46 Olomouc, Czech Republic Received July 20, 2009 Abstract: The strengths of noncovalent interactions are generally very sensitive to a number of geometric parameters. Among the most important of these parameters is the separation between the interacting moieties (in the case of an intermolecular interaction, this would be the intermolecular separation). Most works seeking to characterize the properties of intermolecular interactions are mainly concerned with binding energies obtained at the potential energy minimum (as determined at some particular level of theory). In this work, in order to extend our understanding of these types of noncovalent interactions, we investigate the distance dependence of several types of intermolecular interactions, these are hydrogen bonds, stacking interactions, dispersion interactions, and X-H ··· π interactions. There are several methods that have traditionally been used to treat noncovalent interactions as well as many new methods that have emerged within the past three or four years. Here we obtain reference data using estimated CCSD(T) values at the complete basis set limit (using the CBS(T) method); potential energy curves are also produced using several other methods thought to be accurate for intermolecular interactions, these are MP2/cc- pVTZ, MP2/aug-cc-pVDZ, MP2/6-31G*(0.25), SCS(MI)-MP2/cc-pVTZ, estimated MP2.5/CBS, DFT-SAPT/ aug-cc-pVTZ, DFT/M06-2X/6-311+G(2df,2p), and DFT-D/TPSS/6-311++G(3df,3pd). The basis set superposition error is systematically considered throughout the study. It is found that the MP2.5 and DFT- SAPT methods, which are both quite computationally intensive, produce potential energy curves that are in very good agreement to those of the reference method. Among the MP2 techniques, which can be said to be of medium computational expense, the best results are obtained with MP2/cc-pVTZ and SCS(MI)-MP2/cc-pVTZ. DFT-D/TPSS/6-311++G(3df,3pd) is the DFT-based method that can be said to give the most well-balanced description of intermolecular interactions. Introduction The structure, stability, and dynamic properties of biomo- lecular systems, such as proteins, DNA/RNA, and protein-ligand complexes, are influenced by several physical factors, the most important of which are solvation effects 1,2 and non- covalent interactions. 3–6 The mode of action of solvation effects in stabilizing biomacromolecules is generally seen * Corresponding author. E-mail: kev.e.riley@gmail.com (K.E.R.); pavel.hobza@uochb.cas.cz (P.H.). † Department of Chemistry, University of Puerto Rico. ‡ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and Center of Biomolecules and Complex Molecular Systems. § Department of Physical and Theoretical Chemistry, Comenius University. | Institute of Biotechnology, Academy of Sciences of the Czech Republic. ⊥ Department of Physical Chemistry, Palacky ´ University. J. Chem. Theory Comput. 2010, 6, 66–80 66 10.1021/ct900376r  2010 American Chemical Society Published on Web 12/09/2009