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We present self-consistent reaction field (SCRF) calculations, utilizing correlated ab initio quantum mechanics, of aqueous solvation free energies for a large data base of molecular solutes. We identify a subset of chemical functional groups for which there are systematic deviations in the comparison of theory and experiment; furthermore, for one case which has been extensively investigated, methylated amines, similar deviations appear in explicit solvent free energy perturbation calculations employing several commonly used molecular mechanics potential functions. By carrying out high-level ab initio quantum chemical calculations of hydrogen-bonding energies of the solutes to a water molecule, we arrive at a coherent explanation of the disagreements between theory and experiment, namely, that hydrogen-bonding energies are in some cases poorly correlated with classical electrostatic interaction energies. We show that the deviation in hydrogen-bonding energies of a solute from a reference molecule (for which there is good agreement between the SCRF calculations and experiment) is an excellent predictor of the errors made for that solute in the SCRF calculations. A new SCRF model is developed in which short-range empirical corrections, based upon solvent accessibility, are made for these chemical functional groups; this reduces the mean error of the calculated solvation free energies for the entire data base by a factor of ∼2, to 0.37 kcal/mol. These results have significant implications for the accuracy of explicit solvent potential functions as well as dielectric continuum models. Finally, we also identify cases where the observed discrepancies in solvation free energies cannot be explained by pair hydrogen-bonding results and suggest problems here that may be specific to dielectric continuum theory.

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The energy of dimerization of two N-methylacetamide (NMA) molecules in vacuum is calculated using density functional theory. Natural orbital analysis suggests that the dimerization energy of -6.6 kcal/mol is predominantly due to the (NsH‚‚‚OdC) donor-acceptor interaction. The gas phase to water hydration free energies and the free energies of transfer from the aqueous phase to liquid alkane of hydrogen bonded, (NsH‚‚‚OdC), and nonbonded, (NsH,OdC), groups are calculated using a continuum solvent model. On the basis of these calculations, we estimate the free energy of forming an amide hydrogen bond in the context of the NMA dimer in water and in liquid alkane as ∼-1 and ∼-5 kcal/mol, respectively. The relevance of these calculations to processes such as protein folding and membrane insertion of proteins is discussed.

The FDPB/γ method and the PARSE parameter set have been recently shown to provide a computationally efficient and accurate means of calculating hydration free energies. In this paper this approach is extended to the treatment of the partitioning of various solute molecules between the gas phase, water, and alkane solvents. The FDPB/γ method treats the solute molecule as a polarizable cavity embedded in a dielectric continuum. The solute charge distribution is described in terms of point charges located at atomic nuclei. Electrostatic free energies are obtained from numerical (finite difference) solutions to the Poisson (or Poisson−Boltzmann) equation, while nonpolar contributions are treated with a surface area-dependent term proportional to a surface tension coefficient, γ. To apply the FDPB/γ method to nonaqueous phases, it is necessary to derive a continuum representation of solute−solvent interactions appropriate for such systems. It is argued in this work that solute cavities in nonpolar solvents are significantly larger than in aqueous media. The physical basis for the existence of an expanded cavity in nonpolar solvents is discussed. When an expanded cavity, described in terms of increased values for atomic radii, is incorporated into the FDPB/γ formalism, good agreement between calculated and experimental solvation free energies is obtained. A new PARSE parameter set is developed for the transfer of organic molecules between alkanes and water which yields an average absolute error in solvation free energies of 0.2 kcal/mol for the 18 small molecules for which the parameters were optimized.

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An open question in protein homology modeling is, how well do current modeling packages satisfy the dual criteria of quality of results and practical ease of use? To address this question objectively, we examined homology-built models of a variety of therapeutically relevant proteins. The sequence identities across these proteins range from 19% to 76%. A novel metric, the difference alignment index (DAI), is developed to aid in quantifying the quality of local sequence alignments. The DAI is also used to construct the relative sequence alignment (RSA), a new representation of global sequence alignment that facilitates comparison of sequence alignments from different methods. Comparisons of the sequence alignments in terms of the RSA and alignment methodologies are made to better understand the advantages and caveats of each method. All sequence alignments and corresponding 3D models are compared to their respective structurebased alignments and crystal structures. A variety of protein modeling software was used. We find that at sequence identities >40%, all packages give similar (and satisfactory) results; at lower sequence identities (<25%), the sequence alignments generated by Profit and Prime, which incorporate structural information in their sequence alignment, stand out from the rest. Moreover, the model generated by Prime in this low sequence identity region is noted to be superior to the rest. Additionally, we note that DSModeler and MOE, which generate reasonable models for sequence identities >25%, are significantly more functional and easier to use when compared with the other structure-building software.Keywords: homology modeling; comparative modeling; sequence alignments; protein modeling software; software usability Despite significant progress in X-ray crystallography and high-field NMR spectroscopy for solving protein structures (Berman et al. 2000; also http://www.rcsb.org/pdb/ holdings.html), structures for many therapeutically relevant target receptors remain unavailable. Such structures are particularly desirable in the early phases of drug discovery projects before experimental structural methods are in place, and one therefore has to rely on comparative modeling based on homologous templates for constructing three-dimensional (3D) models (Hillisch and Hilgenfeld 2003;Hillisch et al. 2004). The performance of homology modeling is well understood and documented (Johnson et al. 1994;Congreve et al. 2005). The method relies on the observation that in nature the structural conformation of a protein is more highly conserved than its amino acid sequence, and that small or medium changes in sequence typically result in only small changes in the 3D structure Reprint requests to: Akbar Nayeem, Bristol-Myers Squibb,