A hierarchy of three models for combined quantum mechanical (QM) and molecular mechanical (MM) approaches is presented. They simplify the QM description of large molecules by reducing it to the electronically important fragment which interacts with the molecular mechanically treated remainder of the molecule. In the simplest model A, the QM fragments are only mechanically embedded in their MM environment. The more refined models B and C include a quantum mechanical treatment of electrostatic interactions between the fragments and a semiclassical description of polarization. The implementation of models A-C for MNDO type wavefunctions and the MM3 force field is outlined. Selected applications in organic chemistry are discussed, addressing the ability of the proposed models to reproduce substituent effects (MM) on chemical structure and reactivity (QM). These applications include protonations, deprotonations, hydride transfer reactions, nucleophilic additions, and nucleophilic ring cleavage reactions

We present the latest version of the Groningen Molecular Simulation program package, GROMOS05. It has been developed for the dynamical modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization. An overview of GROMOS05 is given, highlighting features not present in the last major release, GROMOS96. The organization of the program package is outlined and the included analysis package GROMOS++ is described. Finally, some applications illustrating the various available functionalities are presented.

Computation based on molecular models is playing an increasingly important role in biology, biological chemistry, and biophysics. Since only a very limited number of properties of biomolecular systems is actually accessible to measurement by experimental means, computer simulation can complement experiment by providing not only averages, but also distributions and time series of any definable quantity, for example, conformational distributions or interactions between parts of systems. Present day biomolecular modeling is limited in its application by four main problems: 1) the force-field problem, 2) the search (sampling) problem, 3) the ensemble (sampling) problem, and 4) the experimental problem. These four problems are discussed and illustrated by practical examples. Perspectives are also outlined for pushing forward the limitations of biomolecular modeling.

A theoretical composite approach, termed ATOMIC for Ab initio Thermochemistry using Optimal-balance Models with Isodesmic Corrections, is introduced for the calculation of molecular atomization energies and enthalpies of formation. Care is taken to achieve optimal balance in accuracy and cost between the various components contributing to high-level estimates of the fully correlated energy at the infinite-basis-set limit. To this end, the energy at the coupled-cluster level of theory including single, double, and quasiperturbational triple excitations is decomposed into Hartree-Fock, low-order correlation (MP2, CCSD), and connected-triples contributions and into valence-shell and core contributions. Statistical analyses for 73 representative neutral closed-shell molecules containing hydrogen and at least three first-row atoms (CNOF) are used to devise basis-set and extrapolation requirements for each of the eight components to maintain a given level of accuracy. Pople's concept of bond-separation reactions is implemented in an ab initio framework, providing for a complete set of high-level precomputed isodesmic corrections which can be used for any molecule for which a valence structure can be drawn. Use of these corrections is shown to lower basis-set requirements dramatically for each of the eight components of the composite model. A hierarchy of three levels is suggested for isodesmically corrected composite models which reproduce atomization energies at the reference level of theory to within 0.1 kcal/mol (A), 0.3 kcal/mol (B), and 1 kcal/mol (C). Large-scale statistical analysis shows that corrections beyond the CCSD(T) reference level of theory, including coupled-cluster theory with fully relaxed connected triple and quadruple excitations, first-order relativistic and diagonal Born-Oppenheimer corrections can normally be dealt with using a greatly simplified model that assumes thermoneutral bond-separation reactions and that reduces the estimate of these corrections to the simple task of adding up bond increments. Preliminary validation with experimental enthalpies of formation using the subset of neutral closed-shell (HCNOF) species contained in the G3/99 test set indicates that the ATOMIC protocol performs slightly better than the popular G3 approach. The newly introduced protocol does not require empirical calibration, however, and it is still efficient enough to be applied routinely to molecules with 10 or 20 nonhydrogen atoms.

How do enzymes achieve very large rate enhancements compared to corresponding uncatalyzed reactions in solution? We present a computational approach which combines high-level ab initio quantum mechanical calculations with classical free energy calculations to address this question. Our calculations lead to accurate estimates of DeltaG for both trypsin and catechol O-methyltransferase-catalyzed and reference uncatalyzed reactions and give new insights into the nature of enzyme catalysis. The same methodology applied to steps in the catalytic mechanism of citrate synthase further supports the conclusion that one need not invoke special concepts such as "low-barrier hydrogen bonds" or "pK(a) matching" to explain enzyme catalysis.

Base-catalyzed hydrolysis of formamide in the gas phase and in aqueous solution has been studied using a combination of quantum chemical and statistical mechanical methods. A three-step procedure has been applied which comprises the determination of a gas-phase reaction path by high-level ab initio calculations, the calibration of empirical solute-solvent potentials, and classical Monte Carlo simulations of the solute immersed in a bath of solvent molecules. These simulations yield the solvent effect as a potential of mean force along the predetermined reaction coordinate. Each of the three consecutive steps of base-catalyzed hydrolysis has been analyzed in detail: the formation of a tetrahedral intermediate, its conformational isomerization, and the subsequent breakdown to products. The reaction is very exothermic in the gas phase and involves only moderate barriers for the latter two steps. Aqueous solvent, however, induces a significant barrier toward formation of the intermediate. On the other hand, it also facilitates conformational isomerization and produces a more product-like transition state for the breakdown step. Solvent effects, as expressed by differences in free energy of solvation, are found to reflect variations in the solute's charge distribution and are readily explained by the analysis of hydrogen bond patterns. The calculated free energy profile is in satisfactory agreement with available experimental data for the solution-phase reaction.

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The recently proposed ATOMIC protocol is a fully ab initio thermochemical approach designed to provide accurate atomization energies for molecules with well-defined valence structures. It makes consistent use of the concept of bond-separation reactions to supply high-level precomputed bond increments which correct for errors of lower-level models. The present work extends the approach to the calculation of standard heats of formation and validates it by comparison to experimental and benchmark level ab initio data reported in the literature. Standard heats of formation (298 K) have been compiled for a large sample of 173 neutral molecules containing hydrogen and first-row atoms (C, N, O, F), resorting to several previous compilations and to the original experimental literature. Statistical evaluation shows that the simplest implementation of the ATOMIC protocol (composite model C) achieves an accuracy comparable to the popular Gaussian-3 approach and that composite models A and B perform better. Chemical accuracy (1-2 kcal/mol) is normally achieved even for larger systems with about 10 non-hydrogen atoms and for systems with charge-separated valence structures, bearing testimony to the robustness of the bond-separation reaction model. Effects of conformational averaging have been examined in detail for the series of n-alkanes, and our most refined composite model A reproduces experimental heats of formation quantitatively, provided that conformational averaging is properly accounted for. Several cases of larger discrepancy with respect to experiment are discussed, and potential weaknesses of the approach are identified.