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Simulating the dielectric spectra of solvents requires the nuanced definition of inter- and intra-molecular forces. Non-polarizable force fields, while thoroughly benchmarked for dielectric applications, do not capture all the spectral features of solvents, such as water. Conversely, polarizable force fields have been largely untested in the context of dielectric spectroscopy but include charge and dipole fluctuations that contribute to intermolecular interactions. We benchmark non-polarizable force fields and the polarizable force fields AMOEBA03 and HIPPO for liquid water and find that the polarizable force fields can capture all the experimentally observed spectral features with varying degrees of accuracy. However, the non-polarizable force fields miss at least one peak. To diagnose this deficiency, we decompose the liquid water spectra from polarizable force fields at multiple temperatures into static and induced dipole contributions and find that the peak originates from induced dipole contributions. Broadening our inquiry to other solvents parameterized with the AMOEBA09 force field, we demonstrate good agreement between the experimental and simulated dielectric spectra of methanol and formamide. To produce these spectra, we develop a new computational approach to calculate the dielectric spectrum via the fluctuation dissipation theorem. This method minimizes the error in both the low and high frequency portions of the spectrum, improving the overall accuracy of the simulated spectrum and broadening the computed frequency range. [ABSTRACT FROM AUTHOR]

A robust approach for dealing with electrostatic interactions for spherical boundary conditions has been implemented in the QM/MM framework. The development was based on the generalized solvent boundary potential (GSBP) method proposed by Im et al. [J. Chem. Phys. 114, 2924 (2001)], and the specific implementation was applied to the self-consistent-charge density-functional tight-binding approach as the quantum mechanics (QM) level, although extension to other QM methods is straightforward. Compared to the popular stochastic boundary-condition scheme, the new protocol offers a balanced treatment between quantum mechanics/molecular mechanics (QM/MM) and MM/MM interactions; it also includes the effect of the bulk solvent and macromolecule atoms outside of the microscopic region at the Poisson–Boltzmann level. The new method was illustrated with application to the enzyme human carbonic anhydrase II and compared to stochastic boundary-condition simulations using different electrostatic treatments. The GSBP-based QM/MM simulations were most consistent with available experimental data, while conventional stochastic boundary simulations yielded various artifacts depending on different electrostatic models. The results highlight the importance of carefully treating electrostatics in QM/MM simulations of biomolecules and suggest that the commonly used truncation schemes should be avoided in QM/MM simulations, especially in simulations that involve extensive conformational samplings. The development of the GSBP-based QM/MM protocol has opened up the exciting possibility of studying chemical events in very complex biomolecular systems in a multiscale framework. [ABSTRACT FROM AUTHOR]

An osmometric method and a water-accessible surface area (ASA) analysis are developed to quantify and interpret the interactions of the remarkable osmolyte glycine betaine (GB) with molecular surfaces in water. GB, lacking hydrogen bond donors which is unable to compete with water to interact with anionic and amide oxygen demonstrated its effectiveness as an osmolyte in the Escherichia coli cytoplasm.

Potential of mean force (PMF) calculations and a calibrated quantum mechanical and molecular mechanical (QM/MM) potential are used for studying the proton transfer energetics in carbonic anhydrase II (CAII) associated with different orientations of the acceptor group. The results of the perturbation analysis and the [PHI] analysis have tested the mechanistic proposals in which the stepwise proton hole transfer pathway is proposed.

A proton transfer through water is achieved by generating a hydroxide by first protonating the acceptor and then transferring the hydroxide toward the donor through water that is described as the transfer of a 'proton hole' from the acceptor to the donor. The study establishes that the 'proton hole' transfer is important for proton transport in many complex molecular systems.

Effective quantum mechanical/molecular mechanical (QM/MM) methods were studied in order to understand vectorial proton transport in biomolecular ion pumps. It was found that quantitative energetics and new mechanistic insights can be obtained for complex processes that involve the ionization and transfer of protons in water and the enzyme carbonic anhydrase and the fluctuations of water molecules peripheral to the water wire were found to make larger impact on the proton transfer energetics.

The overall goal of the study is to rigorously test typical quantum mechanical and molecular mechanics (QM/MM) protocols in order to provide a clear picture of the accuracy and relative importance of various factors in determining the accuracy. The results will provide useful guidance to the quantitative application of QM/MM simulations in general.

The importance of treating van der Waals interactions between the quantum mechanical (QM) and molecular mechanical (MM) atoms in hybrid QM/MM simulations is investigated. The study indicates that the efforts in improving the reliability of QM/MM methods for energetical properties in the condensed phase should focus on components other than van der Waals interactions between QM and MM atoms.

The quasi-chemical theory and electronic structure outcome on inner-sphere H(H2O)(sub n)(super +) group are used to discuss the absolute hydration free energy of H(super +)(aq). It is observed that this volume is not thermodynamically measurable which results in improper alignment of tables of absolute hydration free energies of ions in water.

Many proteins use corrinoid cofactors to facilitate methyl transfer reactions. Recently, a corrinoid protein, HgcA, has been shown to be required for the production of the neurotoxin methylraercury by anaerobic bacteria. A strictly conserved Cys residue in HgcA was predicted to be a lower-axial ligand to Co(III), which has never been observed in a corrinoid protein. Here, we use density functional theory to study homolytic and heterolytic Co--C bond dissociation and methyl transfer to Hg(II) substrates with model methylcobalamin complexes containing a lower-axial Cys or His ligand to cobalt, the latter of which is commonly found in other corrinoid proteins. We find that Cys thiolate coordination to Co facilitates both methyl radical and methyl carbanion transfer to Hg(II) substrates, but carbanion transfer is more favorable overall in the condensed phase. Thus, our findings are consistent with HgcA representing a new class of corrinoid protein capable of transferring methyl groups to electrophilic substrates. [ABSTRACT FROM AUTHOR]

Many proteins use corrinoid cofactors to facilitate methyl transfer reactions. Recently, a corrinoid protein, HgcA, has been shown to be required for the production of the neurotoxin methylmercury by anaerobic bacteria. A strictly conserved Cys residue in HgcA was predicted to be a lower-axial ligand to Co(III), which has never been observed in a corrinoid protein. Here, we use density functional theory to study homolytic and heterolytic Co-C bond dissociation and methyl transfer to Hg(II) substrates with model methylcobalamin complexes containing a lower-axial Cys or His ligand to cobalt, the latter of which is commonly found in other corrinoid proteins. We find that Cys thiolate coordination to Co facilitates both methyl radical and methyl carbanion transfer to Hg(II) substrates, but carbanion transfer is more favorable overall in the condensed phase. Thus, our findings are consistent with HgcA representing a new class of corrinoid protein capable of transferring methyl groups to electrophilic substrates.

The accuracy of biological simulations depends, in large part, on the treatment of electrostatics. Due to the availability of accurate experimental values, calculation of pKa provides stringent evaluation of computational methods. The generalized solvent boundary potential (GSBP) and Ewald summation electrostatic treatments were recently implemented for combined quantum mechanical and molecular mechanics (QM/MM) simulations by our group. These approaches were tested by calculating pKa shifts due to differences in electronic structure and electrostatic environment; the shifts were determined for a series of small molecules in solution, using various electrostatic treatments, and two residues (His 31, Lys 102) in the M102K T4-lysozyme mutant with large pKa shifts, using the GSBP approach. The calculations utilized a free energy perturbation scheme with the QM/MM potential function involving the self-consistent charge density functional tight binding (SCC-DFTB) and CHARMM as the QM and MM methods, respectively. The study of small molecules demonstrated that inconsistent electrostatic models produced results that were difficult to correct in a robust manner; by contrast, extended electrostatics, GSBP, and Ewald simulations produced consistent results once a bulk solvation contribution was carefully chosen. In addition to the electrostatic treatment, the pKa shifts were also sensitive to the level of the QM method and the scheme of treating QM/MM Coulombic interactions; however, simple perturbative corrections based on SCC-DFTB/CHARMM trajectories and higher level single point energy calculations were found to give satisfactory results. Combining all factors gave a root-mean-square difference of 0.7 pKa units for the relative pKa values of the small molecules compared to experiment. For the residues in the lysozyme, an accurate pKa shift was obtained for His 31 with multiple nanosecond simulations. For Lys 102, however, the pKa shift was estimated to be too large, even after more than 10 nanosecond simulations for each lambda window; the difficulty was due to the significant, but slow, reorganization of the protein and water structure when Lys 102 was protonated. The simulations support that Lys 102 is deprotonated in the X-ray structure and the protein is highly destabilized when this residue is protonated.