Local stretching modes for 69 different DH single bonds and 58 H···A H‐bonds are calculated at the ωB97X‐D/aug‐cc‐pVTZ level of theory to describe the changes in donor D and acceptor A upon forming the hydrogen‐bonded complex. The intrinsic strength of the DH and AH interactions is determined utilizing the properties of a well‐defined set of local, uncoupled vibrational modes. The local mode stretching force constant ka(HA) provides a unique measure of bond strength for both covalently and electrostatically bonded complexes. Generally applicable bond orders are derived, which can be related to the binding energies of the hydrogen bonded complexes. Although the red shifts in the DH stretching frequencies can be used to detect hydrogen bonding, they are not sufficient to assess the strength of hydrogen bonding. It is demonstrated that the calculated BSSE‐corrected binding energies of hydrogen bonded complexes are related to the sum of bond order changes caused by hydrogen bonding. The covalent character of charge assisted hydrogen bonds is explained. Because local mode frequencies can also be derived from experimental normal mode frequencies, a new dimension in the study of hydrogen bonding is gained. © 2012 Wiley Periodicals, Inc.

Combined quantum mechanical and molecular mechanical (QM/MM) simulations of N-methylacetamide in aqueous solution have been carried out to investigate the charge polarization of the solute and to explore the feasibility of hybrid QM/MM calculations using ab initio methods. In the present study, the ab initio Hartree−Fock theory along with the 3-21G basis set was used in the quantum mechanical calculations. Statistical mechanical Monte Carlo approach was then applied in molecular mechanical simulations, employing the empirical TIP3P model for water. Comparisons with results obtained from the hybrid semiempirical Austin model 1 (AM1)/TIP3P and Jorgensen's OPLS (optimized potential for liquid simulations) potential were made, and a good accord among the three methods has been obtained. The solute charge polarization was analyzed through population analyses and determination of polarization energies. We found that the polarization effects contribute 10−15% to the total solute−solvent interaction energy for N-methylacetamide in water.

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Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.

A combined DFT quantum mechanical and AMBER molecular mechanical potential (QM/MM) is presented for use in molecular modeling and molecular simulations of large biological systems. In our approach we evaluate Lennard-Jones parameters describing the interaction between the quantum mechanical (QM) part of a system, which is described at the B3LYP/6-31+G* level of theory, and the molecular mechanical (MM) part of the system, described by the AMBER force field. The Lennard-Jones parameters for this potential are obtained by calculating hydrogen bond energies and hydrogen bond geometries for a large set of bimolecular systems, in which one hydrogen bond monomer is described quantum mechanically and the other is treated molecular mechanically. We have investigated more than 100 different bimolecular systems, finding very good agreement between hydrogen bond energies and geometries obtained from the combined QM/MM calculations and results obtained at the QM level of theory, especially with respect to geometry. Therefore, based on the Lennard-Jones parameters obtained in our study, we anticipate that the B3LYP/6-31+G*/AMBER potential will be a precise tool to explore intermolecular interactions inside a protein environment.