Solvation nucleic acid

Within the last decade important progress has been made in the reliability of MD simulations of solvated nucleic acids using improved force fields and, in particular, a better treatment of electrostatics by the particle-mesh Ewald method. For the first time unrestrained simulations have become possible. Starting out firom experimental geometries it is now possible to explore the conformational space in the vicinity of the starting geometry and to study conformational transitions. ... 

An understanding of a wide variety of phenomena concerning conformational stabilities and molecule-molecule association (protein-protein, protein-ligand, and protein-nucleic acid) requires consideration of solvation effects. In particular, a quantitative assessment of the relative contribution of hydrophobic and electrostatic interactions in macromolecular recognition is a problem of central importance in biology. 

The use of computer simulations to study internal motions and thermodynamic properties is receiving increased attention. One important use of the method is to provide a more fundamental understanding of the molecular information contained in various kinds of experiments on these complex systems. In the first part of this paper we review recent work in our laboratory concerned with the use of computer simulations for the interpretation of experimental probes of molecular structure and dynamics of proteins and nucleic acids. The interplay between computer simulations and three experimental techniques is emphasized (1) nuclear magnetic resonance relaxation spectroscopy, (2) refinement of macro-molecular x-ray structures, and (3) vibrational spectroscopy. The treatment of solvent effects in biopolymer simulations is a difficult problem. It is not possible to study systematically the effect of solvent conditions, e.g. added salt concentration, on biopolymer properties by means of simulations alone. In the last part of the paper we review a more analytical approach we have developed to study polyelectrolyte properties of solvated biopolymers. The results are compared with computer simulations. 

Orozco, M. Colominas, C. Luque, F. J., Theoretical determination of the solvation free energy in water and chloroform of the nucleic acid bases, Chem. Phys. 1996, 9, 209-678. 

V. Tsui and D. A. Case, Molecular dynamics simulations of nucleic acids with a generalized bom solvation model, J. Am. Chem. Soc. 122 2489 (2000). 

Solvation Free Energies of Nucleic Acid Bases and Amino Acid Side-Chains... 

Figure 3. Nucleic acid bases used in solvation free energy calculations.

J. L. Miller and P. A. Kollman, Solvation free energies of the nucleic acid bases, J. Phys. 

The specific processes discussed above are all special cases of the general process (9.2.1). In all of these cases we have seen the explicit modification of the equilibrium constant of the corresponding process. As indicated in Eq. (9.2.3), the general modification requires knowledge of the solvation Gibbs energies of all the components involved in the process. For macromolecules such as proteins or nucleic acid, none of these is known, however. Nevertheless, some specific solvation effects are examined in Sections 9.4 and 9.5. 

In the majority of continuum solvation models incorporating a surface-tension approach to estimating the non-electrostatic solvation components, the index k in Eq. (11.22) runs over a list of atom types, and die user assigns the appropriate type to each atom of the solute. This is particularly straightforward for MM models, like the Generalized Bom/Surface Area (GB/SA) model (Still el al. 1990 see also Best, Merz, and Reynolds 1997), since atom types are already intrinsic to the force field approach. This same formalism has been combined with the CHARMM and Cornell et al. force fields (see Table 2.1) to define GB models for proteins and nucleic acids (Dominy and Brooks 1999 Jayaram, Sprous, and Beveridge 1998). Considering this approach applied within the QM arena, the MST-ST models of Orozco and Luque have been the most extensively developed (see, for instance, Curutchet, Orozco, and Luque 2001). 

Table 11.3 Absolute free energies of solvation (kcal mol ) and chloroform/water partition coefficients (logio units) for nucleic acid bases at the SM5.4/AM1 Icvcf ...

Li, J. Cramer, and Truhlar, D. G. 1999. Application of a Universal Solvation Model to Nucleic Acid Bases. Comparison of Semiempirical Molecular Orbital Theory, Ab Initio, Hartree-Fock Theory, and Density Functional Theory , Biophys. Chem.. 78, 147. 

Of course, the simplicity of the QM/MM operator does not imply diat it has only a small effect. Large atomic partial charges placed near the QM fragment would be expected to polarize the system strongly. Table 13.2 compares the dipole moments of the standard nucleic acid bases at the AMI level evaluated in the gas phase and in a QM/MM calculation carried out modeling aqueous solvation with a periodic box of TIP31 water molecules. Eor comparison, results from the AM1-SM2 aqueous continuum solvation model are also provided. 

It is important to recognize how a QM/MM calculation like that for the nucleic acid base solvated dipole moments is accomplished. We outline here a typical series of steps... 

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