Here, we present the algorithm and validation for OMEGA, a systematic, knowledge-based conformer generator. The algorithm consists of three phases: assembly of an initial 3D structure from a library of fragments; exhaustive enumeration of all rotatable torsions using values drawn from a knowledge-based list of angles, thereby generating a large set of conformations; and sampling of this set by geometric and energy criteria. Validation of conformer generators like OMEGA has often been undertaken by comparing computed conformer sets to experimental molecular conformations from crystallography, usually from the Protein Databank (PDB). Such an approach is fraught with difficulty due to the systematic problems with small molecule structures in the PDB. Methods are presented to identify a diverse set of small molecule structures from cocomplexes in the PDB that has maximal reliability. A challenging set of 197 high quality, carefully selected ligand structures from well-solved models was obtained using these methods. This set will provide a sound basis for comparison and validation of conformer generators in the future. Validation results from this set are compared to the results using structures of a set of druglike molecules extracted from the Cambridge Structural Database (CSD). OMEGA is found to perform very well in reproducing the crystallographic conformations from both these data sets using two complementary metrics of success.

This article shows how to evaluate rotational symmetry numbers for different molecular configurations and how to apply them to transition state theory. In general, the symmetry number is given by the ratio of the reactant and transition state rotational symmetry numbers. However, special care is advised in the evaluation of symmetry numbers in the following situations: (i) if the reaction is symmetric, (ii) if reactants and/or transition states are chiral, (iii) if the reaction has multiple conformers for reactants and/or transition states and, (iv) if there is an internal rotation of part of the molecular system. All these four situations are treated systematically and analyzed in detail in the present article. We also include a large number of examples to clarify some complicated situations, and in the last section we discuss an example involving an achiral diasteroisomer.

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Practical approximation schemes for calculating partition functions of torsional modes are tested against accurate quantum mechanical results for H(2)O(2) and six isotopically substituted hydrogen peroxides. The schemes are classified on the basis of the type and amount of information that is required. First, approximate one-dimensional hindered-rotator partition functions are benchmarked against exact one-dimensional torsion results obtained by eigenvalue summation. The approximate one-dimensional methods tested in this stage include schemes that only require the equilibrium geometries and frequencies, schemes that also require the barrier heights of internal rotation, and schemes that require the whole one-dimensional torsional potential. Then, three classes of approximate full-dimensional vibrational-rotational partition functions are calculated and are compared with the accurate full-dimensional path integral partition functions. These three classes are (1) separable approximations combining harmonic oscillator-rigid rotator models with the one-dimensional torsion schemes, (2) almost-separable approximations in which the nonseparable zero-point energy is used to correct the separable approximations, and (3) improved nonseparable Pitzer-Gwinn-type methods in which approaches of type 1 are used as reference methods in the Pitzer-Gwinn approach. The effectiveness of these methods for the calculation of isotope effects is also studied. Based on the results of these studies, the best schemes of each type are recommended for further use on systems where a corresponding amount of information is available.

Rate constants and (12)C/(13)C kinetic isotope effects are calculated by direct dynamics for the OH + CH(4) --> H(2)O + CH(3) reaction. The electronic structure calculations required to generate the implicit potential energy surface were carried out by the high-level multicoefficient Gaussian-3/version-3 (MCG3) method and compared to two other multilevel methods, MC3BB and MC3MPW, and three density functional methods, M06-2X, BB1K, and MPW1K. The rate constants and (12)C/(13)C kinetic isotope effects are shown to depend strongly on the coordinate system used to calculate the frequencies as well as on the method used to account for the torsional anharmonicity of the lowest-frequency vibrational mode of the generalized transition states.