High-level (MP2, HF, and BLYP with the aug-cc-pVDZ basis set) quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations of liquid water are used here to test the compatibility of various QM methods with four standard empirical “molecular mechanics” (MM) water models. Consistency of QM methods with water models is of particular importance, given the aqueous environment of many of the systems of interest for QM/MM modeling (e.g., biological systems). The results show that treating a single water molecule using a QM method in bulk TIP3P can induce solvent structuring consistent with experiment. The results also show that the TIP4P model is the most suitable water model of those tested for such QM/MM simulations, while the TIP5P model is not well suited. The findings have important implications for future QM/MM method development and applications. They indicate that the choice of MM models should be made carefully for consistency and compatibility in QM/MM simulations.

Molecular simulation is increasingly demonstrating its practical value in the investigation of biological systems. Computational modelling of biomolecular systems is an exciting and rapidly developing area, which is expanding significantly in scope. A range of simulation methods has been developed that can be applied to study a wide variety of problems in structural biology and at the interfaces between physics, chemistry and biology. Here, we give an overview of methods and some recent developments in atomistic biomolecular simulation. Some recent applications and theoretical developments are highlighted.

The applicability of combined quantum mechanics/molecular mechanics (QM/MM) methods for the calculation of absolute binding free energies of conserved water molecules in protein/ligand complexes is demonstrated. Here, we apply QM/MM Monte Carlo simulations to investigate binding of water molecules to influenza neuraminidase. We investigate five different complexes, including those with the drugs oseltamivir and peramivir. We investigate water molecules in two different environments, one more hydrophobic and one hydrophilic. We calculate the free-energy change for perturbation of a QM to MM representation of the bound water molecule. The calculations are performed at the BLYP/aVDZ (QM) and TIP4P (MM) levels of theory, which we have previously demonstrated to be consistent with one another for QM/MM modeling. The results show that the QM to MM perturbation is significant in both environments (greater than 1 kcal mol(-1)) and larger in the more hydrophilic site. Comparison with the same perturbation in bulk water shows that this makes a contribution to binding. The results quantify how electronic polarization differences in different environments affect binding affinity and also demonstrate that extensive, converged QM/MM free-energy simulations, with good levels of QM theory, are now practical for protein/ligand complexes.

Combined quantum mechanics/molecular mechanics (QM/MM) methods allow computations on chemical events in large molecular systems. Here, we have tested the suitability of the standard CHARMM27 forcefield Lennard-Jones van der Waals (vdW) parameters for the treatment of nucleic acid bases in QM/MM calculations at the B3LYP/6-311+G(d,p)-CHARMM27 level. Alternative parameters were also tested by comparing the QM/MM hydrogen bond lengths and interaction energies with full QM [B3LYP/6-311+G(d,p)] results. The optimization of vdW parameters for nucleic acid bases is challenging because of the likelihood of multiple hydrogen bonds between the nucleic acid base and a water molecule. Two sets of optimized atomic vdW parameters for polar hydrogen, carbonyl carbon, and aromatic nitrogen atoms for nucleic acid bases are reported: base-dependent and base-independent. The results indicate that, for QM/MM investigations of nucleic acids, the standard forcefield vdW parameters may not be appropriate for atoms treated by QM. QM/MM interaction energies calculated with standard CHARMM27 parameters are found to be too large, by around 3 kcal/mol. This is because of overestimation of electrostatic interactions. Interaction energies closer to the full QM results are found using the optimized vdW parameters developed here. The optimized vdW parameters [developed by reference to B3LYP/6-311+G(d,p) results] were also tested at the B3LYP/6-31G(d) QM/MM level and were found to be transferable to the lower level. The optimized parameters also model the interaction energies of charged nucleic acid bases and deprotonation energies reasonably well.

In many languages, sounds in certain "privileged" positions preserve marked structure which is eliminated elsewhere (Positional Faithfulness, Beckman 1998).  This paper presents new corpus and experimental evidence that faithfulness to main-stress location and segmental content of morpho-semantic heads emerges in English blends. The study compared right-headed (subordinating) blends, like motor + hotel -&gt; motel (a kind of hotel) with coordinating blends like spoon + fork -&gt; spork (equally spoon and fork).<br /><br />Stress: Analysis of 1095 blends from Thurner (1993) found that right-headed blends were more faithful to stress location of the second source word than were coordinating blends.  Given source words with conflicting stress (e.g., FLOUNder + sarDINE), participants preferentially matched the blend that preserved second-word stress (flounDINE) to a right-headed definition.<br /><br />Segmental content: When source-word length was controlled, segments from right-headed blends were more likely to survive than those from coordinating blends.  Given source words that could be spliced at two points (e.g., flaMiNGo + MoNGoose), participants preferentially matched the one that preserved more of the second word (flamongoose) to a right-headed definition.<br /><br />These results support the hypotheses that Positional Faithfulness constraints are universally available, that heads are a privileged position, and that blend phonology is sensitive to headedness.<br /><br />

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Binding free energy predictions have the potential to play pivotal roles in the drug discovery process, ranging from aiding selection of hit molecules from large databases of compounds to optimizing lead structures. Calculation of relative binding free energies from molecular simulations (e.g., molecular dynamics or Monte Carlo simulations), though computationally intensive, have proved their worth in a number of pharmaceutical applications. Despite this, it is now clear that, in many cases, the methods typically used in such simulations to model molecular interactions have significant limitations. For example, in protein–ligand systems in which charge transfer or polarization are important, or where a metal ion is present in the binding site, conventional molecular mechanics (MM) methods may not represent binding accurately. Methods based on quantum mechanics (QM), for all or part of the system, are potentially more accurate. This chapter reviews recent advances in the growing field of calculating or predicting binding free energies using a quantum mechanical (i.e., quantum chemical, electronic structure) treatment of all or part of the system, for example, a QM description of the ligand alone (or with part of the binding site), coupled to a MM treatment of the protein (QM/MM calculations) or a QM description of the entire protein–ligand complex.