Evaluating nonpolarizable nucleic acid force fields: A systematic comparison of the nucleobases hydration free energies and chloroform‐to‐water partition coefficients

Nucleic acid force fields have been shown to reproduce structural properties of DNA and RNA very well, but comparative studies with respect to thermodynamic properties are rare. As a test for thermodynamic properties, we have computed hydration free energies and chloroform‐to‐water partition coefficients of nucleobases using the AMBER‐99, AMBER‐gaff, CHARMM‐27, GROMOS‐45a4/53a6 and OPLS‐AA force fields. A mutual force field comparison showed a very large spread in the calculated thermodynamic properties, demonstrating that some of the parameter sets require further optimization. The choice of solvent model used in the simulation does not have a significant effect on the results. Comparing the hydration free energies obtained by the various force fields to the adenine and thymine experimental values showed a very large deviation for the GROMOS and AMBER parameter sets. Validation against experimental partition coefficients showed good agreement for the CHARMM‐27 parameter set. In view of mutation studies, differences in partition coefficient between two bases were also compared, and good agreement between experiments and calculations was found for the AMBER‐99 parameter set. Overall, the CHARMM‐27 parameter set performs best with respect to the thermodynamic properties tested here. © 2012 Wiley Periodicals, Inc.     

Photoinduced α-Alkylation of Tetrahydroisoquinolines with Organoboron Reagent Enabled by Organic Photocatalyst

We describe an efficient method for α-functionalization of N-aryl-tetrahydroisoquinolines under visible-light-irradiation catalyzed by organic photocatalyst. This protocol provides a concise and environmental approach for the rapid allylation and benzylation of N-aryl-tetrahydroisoquinolines, and shows broad substrate scope. Stable organoboron reagents have shown their ability in the construction of challenging Csp³−Csp³ bond. The load of the photocatalyst is low and the oxidant is inexpensive and less toxic.     

Efficient calculation of many stacking and pairing free energies in DNA from a few molecular dynamics simulations

Through the use of the one-step perturbation approach, 130 free energies of base stacking and 1024 free energies of base pairing in DNA have been calculated from only five simulations of a nonphysical reference state. From analysis of a diverse set of 23 natural and unnatural bases, it appears that stacking free energies and stacking conformations play an important role in pairing of DNA nucleotides. On the one hand, favourable pairing free energies were found for bases that do not have the possibility to form canonical hydrogen bonds, while on the other hand, good hydrogen-bonding possibilities do not guarantee a favourable pairing free energy if the stacking of the bases dictates an unfavourable conformation. In this application, the one-step perturbation approach yields a wealth of both energetic and structural information at minimal computational cost.     

Free energy perturbation simulations of cation binding to valinomycin

Experimental values of the free energies of cation binding to the cyclic depsipeptide molecule, valinomycin, obtained from Pedersen-type salt extraction measurements, provide data against which it is possible to test the adequacy of the procedures and force fields of the molecular dynamics algorithms, MOLARIS and GROMOS. These data are then used to assess appropriate values for the partial charges of the ester carbonyl oxygen and carbon. Valinomycin was chosen because it has only one kind of ion-binding ligand and because the cation is sufficiently enfolded by the molecule in the ion-complexes that the overall size and shape of the complex is virtually the same regardless of the species of cation bound. For such an isosteric complex, the experimentally measured selectivities are sufficiently similar in a wide variety of solvent environments that thedifferences in free energies measured between the different ion-valinomycin complexes by two-phase salt extraction experiments into dichloromethane can be taken as equivalent to the differences in free energies in vacuo. Thesedifferences were therefore compared with those computed for ion-valinomycin complexationin vacuo by Free Energy Perturbation/Molecular Dynamics (FEP/MD) simulations using the MOLARIS and GROMOS programs. Starting with a set of Lennard-Jones 6–12 parameters for the monovalent cations assessed for aqueous solution we explored the effect of varying the partial charges of the ester carbonyl ligands on binding free energy differences (i.e. the selectivity) among Na, K, Rb, and Cs. The computed selectivity was found to depend strongly on the value of partial charge, following a typical Eisenman Selectivity Pattern in which the correct selectivity sequence and magnitude occurred only over a very narrow range of partial charge (around 0.33 and 0.6 for the standard carbonyls of MOLARIS and GROMOS, respectively). Using MOLARIS we explored the effect of varying the size of the ester carbonyl ligands by comparing the standard carbonyl of MOLARIS with the somewhat smaller carbonyls of GROMOS and found an equally satisfactory ability to reproduce the experimental data with a partial charge value of 0.41. These results validate the use of both the MOLARIS and GROMOS force fields as starting points for quantitative calculations of ion-binding in more complex molecules (e.g., ion-binding sites and channels in proteins).This paper is dedicated to the memory of the late Dr C. J. Pedersen.     

Capturing the Polarization Response of Solvated Proteins under Constant Electric Fields in Molecular Dynamics Simulations

We capture and compare the polarization response of a solvated globular protein ubiquitin to static electric (E-fields) using atomistic molecular dynamics simulations. We collectively follow E-field induced changes, electrical and structural, occurring across multiple trajectories using the magnitude of the protein dipole vector ( P _p ). E-fields antiparallel to P _p induce faster structural changes and more facile protein unfolding relative to parallel fields of the same strength. While weak E-fields (0.1–0.5 V/nm) do not unfold ubiquitin and produce a reversible polarization, strong E-fields (1–2 V/nm) unfold the protein through a pathway wherein the helix:β-strand interactions rupture before those for the β1-β5 clamp. Independent of E-field direction, high E-field induced structural changes are also reversible if the field is switched off before P _p exceeds 2 times its equilibrium value. We critically examine the dependence of water properties, protein rotational diffusion and E-field induced protein unfolding pathways on the thermostat/barostat parameters used in our simulations.     

Interfacing the GROMOS (bio)molecular simulation software to quantum‐chemical program packages

The newly implemented quantum‐chemical/molecular‐mechanical (QM/MM) functionality of the Groningen molecular simulation (GROMOS) software for (bio)molecular simulation is described. The implementation scheme is based on direct coupling of the GROMOS C++ software to executables of the quantum‐chemical program packages MNDO and TURBOMOLE, allowing for an independent further development of these packages. The new functions are validated for different test systems using program and model testing techniques. The effect of truncating the QM/MM electrostatic interactions at various QM/MM cutoff radii is discussed and the application of semiempirical versus density‐functional Hamiltonians for a solute molecule in aqueous solution is compared. © 2012 Wiley Periodicals, Inc.     

A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6

Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.     

Biomolecular modeling: Goals, problems, perspectives

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.